REVIEW For reprint orders, please contact: [email protected]

ALK-positive cancer: still a growing entity Adam Gorczyński1, Monika Prełowska2, Patrick Adam3, Piotr Czapiewski1 & Wojciech Biernat*1

ABSTRACT Since the discovery of ALK-positive anaplastic large-cell lymphoma in 1994 many other types of tumors showing ALK expression were disclosed. They form a heterogeneous group, including lung, renal and soft tissue tumors. The biological function of ALK, its role in carcinogenesis and impact exerted on the clinical outcome have been studied by many research groups. New drugs specifically dedicated for ALK inhibition, for example, crizotinib, have been synthesized and have become a viable treatment option for ALK-positive lung adenocarcinoma, and potentially for other ALK-positive cancers. This review summarizes the current state of knowledge concerning ALK-positive neoplasms, focusing on the clinical aspects of the subject. ALK and its role in pathogenesis of anaplastic large-cell lymphoma (ALCL) was originally described in 1994 by Morris et al. [1]. Since then, it has been a subject of numerous clinical and laboratory studies, which proved that expression of ALK tyrosine kinase can have an impact on morphology, clinical presentation and pathogenesis of many types of cancers, including ALCL [1], non-small-cell lung cancer (NSCLC) [2], neuroblastoma [3], inflammatory myofibroblastic tumors [4] and, most recently, also renal carcinoma. A number of variants of fusion genes were discovered in the past two decades, some of which are used as targets for therapy using newly developed ALK inhibitors.

KEYWORDS

• alkoma • anaplastic

large-cell lymphoma • anaplastic lymphoma kinase • crizotinib • neuroblastoma • renal cell carcinoma

ALK structure & function The ALK gene is located on the 2p23 human chromosome. It encodes a 1620-amino acid protein with a predicted final mass of approximately 200 kDa [5]. ALK is a receptor tyrosine kinase that belongs to the insulin receptor (IR) superfamily. IRs share the specific domains, such as an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic kinase catalytic region which activates the subsequent signaling pathway. ALK has been described as a large, single-chain membrane-spanning receptor tyrosine kinase. In humans the ALK gene is transiently expressed in the CNS. In mice, in situ hybridization studies have detected the murine Alk mRNA expression in multiple regions such as the thalamus, mid-brain and ganglia during the embryonal stage [6]. Thus, it has been suggested to exert an important role in the development of the CNS. Based on murine knockout experiments, Bilsland et al. identified the role of ALK in neurogenesis and cognitive processes. Loss of ALK expression increased the basal hippocampal progenitor proliferation and ALK knockout mice showed an antidepressant profile. ALK was also suggested as a regulator in the frontal cortex and hippocampus dopaminergic signaling system [7]. Department of Pathomorphology, Medical University of Gdańsk, Mariana Smoluchowskiego 17, 80-214, Gdańsk, Poland Department of Molecular Biology, University of Gdańsk, Gdańsk, Poland 3 Institute of Pathology, Comprehensive Cancer Center, University of Tübingen, Tübingen, Germany *Author for correspondence: [email protected] 1 2

10.2217/FON.13.184 © 2014 Future Medicine Ltd

Future Oncol. (2014) 10(2), 305–321

part of

ISSN 1479-6694

305

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat Immunohistochemical studies revealed weak ALK labeling in the normal human tissues such as endothelial cells, pericytes and glial cells in the hypothalamus, cerebral cortex, cerebellum and basal ganglia [8]. In addition, Morris et al. identified ALK transcripts in the human small intestine and less abundant transcripts in the testis, placenta and fetal liver [5]. Subsequent studies have implicated ALK serving as the ligand-dependent receptor regulating apoptosis. In the presence of a ligand, for example, Jeb in Drosophila melanogaster, the ALK receptor kinase becomes activated resulting in decreased apoptosis, while in the absence of the ligand the apoptosis is enhanced [9]. Human ligands of ALK include midkine and PTN [10,11]. Intracellular function of ALK NPM–ALK signaling is the best studied model among all known chimeric ALK proteins so far. It activates several downstream signaling pathways such as PLCg, MAPKs, PI3K/AKT and JAK/STAT. Activation of these pathways results in cell proliferation, prolonged survival, migration and cytoskeletal rearrangements. ●●PLCg

PLCg signaling plays a relevant role in mitogenesis [12]. Activation of phosphoinositide-specific PLC results in production of inositol-1,4,5triphosphate and diacylglycerol, which leads to activation of PKC, Ca 2+ release from intracellular stores and mitogenic signal transmission [13]. The role of PLCg in NPM–ALK-mediated transformation has been proved by Bai et al. [12]. By means of site-directed mutagenesis, they removed the PLCg binding site on NPM–ALK (Tyr664) with subsequent inhibition of the transforming signal. ●●MAPKs

MAPK signaling, activated by receptor tyrosine kinases, is engaged in cell growth, proliferation and differentiation. The signal is triggered by binding various molecules, for example, GrB2, IRS-1 or Shc protein to NPM–ALK. Seemingly the role of IRS-1 and SHC is not as vital for oncogenesis as that performed by GrB2 [14]. Activation of the MAPK pathway, which plays an essential role in ALK-positive ALCL pathogenesis, involves several steps. This intracellular signaling pathway involves two common players in various neoplasms: RAS and ERK. On

306

Future Oncol. (2014) 10(2)

activation of receptor tyrosine kinase (e.g., ALK), an adaptor molecule links the receptor to guanine nucleotide exchange factor SOS, which enables activation of the GTP-binding protein RAS. In turn, RAS activates its effector B-Raf, leading to activation of core signaling mediators MEK1/2 and ERK1/2. ERK induces AP-1 transcription factors such as JUN and FOS, which regulate genes that are important for cell proliferation [15]. Aberrant regulation of this pathway promotes abnormal cell proliferation, which consequently may result in abrogation of cytokine dependence, leukemic transformation and resistance to chemotherapy [16,17]. ●●PI3K/AKT

Activation of PI3K is mediated by direct and indirect interaction of PI3K with NPM–ALK. Activated PI3K converts membrane lipids such as phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-diphoshpate to phosphatidylinositol 3,4-diphosphate and phosphatidylinositol 3,4,5-triphosphate. Newly formed lipids bind to the pleckstrin homology domain of serine/threonine kinase AKT, also known as PKB, which results in AKT recruitment to the plasma membrane. Upon AKT phosphorylation and activation by PDK1, AKT may regulate subsequent downstream mediators such as caspase 9, BAD, NF-kB and Fas ligand [18]. The antiapoptotic function of PI3K/AKT in NPM–ALK transforming activity has been emphasized. AKT prevents cells from apoptosis by phosphorylation and inactivation of the proapoptotic protein BAD [19,20]. Moreover, AKT activation leads to increased degradation of p27, which results in cell cycle progression [21]. In addition, survival effects of NPM–ALK are initiated by mTOR, which is an important regulator of protein translation [18]. The mTOR alternative activation may occur as a step in RAS/ERK pathway [22]. PI3K/AKT enhances cell proliferation by downregulation of FOXO3A, which results in increased cyclin D2 expression and decreased expression of negative cell cycle regulator p27 and proapoptotic protein BIM [15]. PI3K/AKT also enhances activation of the SHH/GLI1 pathway, which constitutive activation was found in ALK-positive ALCL, medulloblastoma, rhabdomyosarcoma, basal cell carcinoma and other malignancies. Inhibition of SHH signaling induces cell cycle arrest and apoptosis in ALK-positive ALCL cell lines. This

future science group

ALK-positive cancer: still a growing entity  suggests that the SHH/GLI1 pathway plays a role in cell survival [23].

Review

with DNA methylation, enhances activation of the JAK/STAT pathway and lymphomagenesis of ALK-positive ALCL [34].

●●JAK/STAT

NPM–ALK triggers enhanced STAT3 activation, which promotes proliferation, cell survival and angiogenesis [24]. STAT3 is a critical factor in malignant transformation and thereby the important target in cancer therapy [25]. This is also supported by the fact that inhibition of the JAK/STAT pathway induces apoptosis and cell cycle arrest in vitro [26,27]. STATs belong to the group of transcription factors activated in response to growth factors and cytokines. Phosphorylation of STATs is mediated by JAKs and leads to STATs detachment from the receptor. STATs dimerize and in this form are translocated to the nucleus where they initiate transcription of antiapoptotic molecules [24]. Activation of STAT3 may occur through JAK3 or may be directly mediated by ALK [26]. The correlation between JAK3 and ALK expression in ALK-positive and -negative ALCL tumors has been highlighted, as the majority of ALK-positive tumors (81%) showed constitutive activation of JAK3 compared to ALK-negative tumors (11%) [28]. Autocrine release of IL-9, which was found in 80% of primary ALK-positive ALCLs, might be at least partially responsible for this, as treatment with a IL-9 inhibitor resulted in decreased JAK3 activation, proliferation and colony formation in ALK-positive ALCL cell lines [29]. STAT3 controls expression of genes involved in regulation of apoptosis and cell cycle progression [30], such as BCL2, BCL-xL, survivin, Mcl-1 and proliferationpromoting cyclin D3, cyclin D1 and c-Myc, as well as cyclin-dependent kinase inhibitor p21WAF [24,25,31]. STAT3 also upregulates inducible iNOS expression by deregulation of post-translational miR-26a-mediated mechanism, which in turn promotes cancer cell survival and carcinogenesis by production of free radical nitric oxide [32]. In addition, STAT3 increases the transcription of VEGF involved in angiogenesis [24]. NPM1-ALK promotes epigenetic silencing through DNA methylation of tumor suppressor STAT5A in malignant cells. Although STAT5B reveals 94% similarity to STAT5A, STAT5B has an opposite role in tumorigenesis as it promotes cell growth and survival [33]. The loss of expression of a negative regulator of JAKs, STATs and SHP1, which is also correlated

future science group

●●Other effectors of NPM–ALK

The interaction between Src-kinases and NPM– ALK has been proven. Src-kinases are the tyrosine kinases involved in NPM–ALK-mediated mitogenesis and might be a possible factor in cell transformation [35]. Another protein interacting with NPM–ALK is IGF-IR. IGF-IR triggers cell survival pathways through the phosphorylation of STAT3, AKT and FKHR, and abnormalities in these proteins are associated with ALK-positive ALCL pathogenesis [36,37]. ALK activation in cancer Several mechanisms may induce the aberrant expression of ALK in neoplasms. Most common are gene rearrangements – that is, translocations occurring as a result of genetic material exchange between two nonhomologous chromosomes and inversions of a chromosomal segment within the chromosome. Both of them result in the generation of fusion genes that may confer an oncogenic potential to the cells [38]. Gene copy gains, or amplifications, can also occur and are typical for neuroblastomas and some histotypes of non-small-cell lung carcinoma [39,40]. The role of miR-96 as a post-transcriptional suppressor of ALK was suggested. A decreased level of miR-96 was observed in ALK-positive tumors and transfection of miR-96 resulted in downregulation of ALK expression [41]. Post-translational mechanisms were also implicated in ALK expression as Hsp-90 inhibitors lowered NPM–ALK expression by inducing its ubiquitin-dependent proteosomal degradation [42]. In normal cells, ALK activation results from binding of ligands, such as PTN and midkine [10,11], but in cancer cells other mechanisms can be responsible for its aberrant activation. ALK point mutations, which were found in neuroblastoma [39], anaplastic thyroid cancer [43] and medulloblastoma [44], result in its constitutive activation. The role of other kinases that are able to induce the ALK activity was mentioned above. Some of them may perform this by direct phosphorylation of ALK [35–37]. Chimeric proteins confer a constitutive signal activation and transduction due to continuous autophosphorylation and activation of ALK kinase domain promoted by the fusion partner (such as NPM) dimerization domain [15].

www.futuremedicine.com

307

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat ALK-positive cancers ●●Anaplastic large-cell lymphoma

ALCL was originally described by Harald Stein and his group in 1985 as a peripheral T-cell lymphoma with high Ki-1 (CD30) expression [45]. In 1989 the t(2;5)(p23;q35) translocation was identified as a hallmark of this lymphoma [46]. Five years later the ALK gene was cloned by Morris et al. and it was determined as a participant of the NPM–ALK fusion gene [1]. This alteration is present in 75–80% of ALK-positive ALCLs and results in fusion of the intracytoplasmic portion of ALK with N-terminal dimerization domain of NPM. NPM is a nuclear chaperon involved in many intracellular processes, including DNA

repair and extranuclear transport of proteins. Alternative but less common translocation participants have been described, including TPM3 [47], TPM4 [48], TFG [49], ATIC [50], CLTC [51], MSN [52], ALO17 [53] and MYH9 (Table 1) [54]. In total, ALK translocations can be found in approximately 50–60% of ALCLs [55]. Since ALK function in ALCL seems to influence the clinical course, ALK-positive and -negative ALCL were separated in the 2008 WHO classification of lymphomas. The rationale for this separation stemmed from the different biology and prognosis characteristic for both forms of these lymphomas [56,57]. ALK-positive ALCL was defined as “a T-cell lymphoma consisting

Table 1. ALK translocations described so far with the typical immunostaining. Disease

Chromosomal abnormality

Fusion gene

Immunohistochemistry

ALCL 

t(2;5)(p23;q35) t(1;2)(q25;p23) t(2;19)(p23;p13) t(2;3)(p23;q21) inv(2)(p23;q35) t(2;17)(p23;q23) t(2;X)(p32;q11–12) t(2;17)(p23;q25) t(2;22)(p23;q11.2) t(2;17)(p23;q23) t(2;5)(p23;q35) ins(4)(2;4)(p23;q21) t(2;5)(p23.1;q35.3) t(2;19)(p23;p13) t(1;2)(q25;p23) t(2;17)(p23;q23) t(2;11;2)

NPM–ALK TPM3–ALK TPM4–ALK TFG–ALK ATIC–ALK CLTC1–ALK MSN–ALK ALO17–ALK MYH9–ALK CLTC–ALK NPM–ALK SEC31A–ALK SQSTM1–ALK TPM4–ALK TPM3–ALK CTLC–ALK CARS–ALK

C/N C C C C C (g) Cell membrane C C C (g) C/N C (g) C (d) C (d) C (d) C (g) –

inv(2)(p23;q35) t(2;2)(p23;q13) , inv(2)(p23;p15;q31) t(2;4)(p23;q21) t(2;12)(p23;p11) inv(2)(p21;p23) t(2;10)(p23;p11) t(2;9)(p23;q31) t(2;14)(p23;q32) t(2;10)(p23;q22) t(1;2)(q25;p23) inv(2)(p21;p23) t(2;19)(p23;p13) inv(2)(p21;p23) inv(2)(p21;p23)

ATIC–ALK RANBP2–ALK SEC31L1–ALK PPFIBP1–ALK EML4–ALK KIF5B–ALK PTPN3–ALK KLC1–ALK VCL–ALK TPM3–ALK EML4–ALK TPM4–ALK EML4–ALK EML4–ALK

C (d) Nuclear membrane C (d) C (d) C C (d) Unknown C (d) C/S C (d/m) C (d/g) – – –

DLBCL

IMT

NSCLC

RCC

ESCC CRC BC

Ref. [1] [47] [48] [49] [50] [51] [52] [53] [54] [68] [69] [70] [71] [4] [4] [84] [53] [85] [86] [88] [87] [93,94] [99] [100] [101] [122] [124] [124] [126,127] [94] [94]

–: ALK labeling was not conducted; ALCL: Anaplastic large-cell lymphoma; BC: Breast carcinoma; C (d): Diffuse cytoplasmic staining; C (d/g): Diffuse cytoplasmic staining with granular accentuation; C (d/m): Diffuse cytoplasmic staining with membranous accentuation; C (g): Granular cytoplasmic staining; C: Cytoplasmic staining, otherwise unspecified; C/N: Cytoplasmic and nuclear staining; CRC: Colorectal carcinoma; DLBCL: Diffuse large B-cell lymphoma; ESCC: Esophageal squamous cell carcinoma; IMT: Inflammatory myofibroblastic tumor; NSCLC: Non-small-cell lung carcinoma; RCC: Renal cell carcinoma.

308

Future Oncol. (2014) 10(2)

future science group

ALK-positive cancer: still a growing entity 

Review

Figure 1. Anaplastic large-cell lymphoma. (A) Typical morphology of ALK-positive anaplastic large-cell lymphoma with cellular pleomorphism and focal presence of horseshoe-like nuclei (arrows). (B) The tumor cells express ALK in the cytoplasm.

of lymphoid cells that are usually large with abundant cytoplasm and pleomorphic, often horseshoe-shaped nuclei, with a translocation involving the ALK gene and expression of ALK and CD30” (Figure 1). In addition, molecular profiles of ALK-positive and -negative ALCL differ, as the former shows overexpression of BCL6, PTPN12, A1AT and CEBPB, whereas the latter presents IL21 and IL22, CCR7 and CNTFR [58]. ALK-positive ALCL occurs more often in children and young adults with male predominance, while ALK-negative ALCL usually affects the middle-aged and older population with a slight prevalence among females [55]. In general, ALK-positive ALCL has a more favorable prognosis than ALK-negative ALCL, with 5-year overall survival amounted to 70–80% and 15–51%, respectively [55,59,60]. Increased ALK expression as well as normal serum LDH levels and IPI score ≤3 were proved to be independent positive prognostic factors in adults [55]. However, this correlation failed in a population of patients over the age of 40 years [61]. Interestingly, extra copies of the ALK gene, regardless whether present in ALK-positive or -negative ALCL, proved to be an independent favorable prognostic marker [62]. An interesting observation of the differences between these two subtypes was provided by ten Berge et al. They studied pathways regulating apoptosis and estimated the expression of caspase 3, Bcl-2 and granzyme B-specific PI-9 expression. ALK-positive ALCL had a significantly higher percentage of caspase 3 activation, whereas expression of the antiapoptotic proteins (BCL-2 and PI-9) was almost exclusive

future science group

to ALK-negative ALCL. These findings strongly emphasize the significance of alterations in the apoptosis pathways that influences favorable response in the former lymphoma subtype and chemoresistance and poorer prognosis frequently found in the latter group [63]. Use of anti-ALK-targeted therapy, namely crizotinib, in ALK-positive ALCL remains a subject of discussion, although good response to such treatment was reported in small groups of two and four patients with recurring ALKpositive ALCL, as well as in one Phase 1 clinical trial [64–66]. ●●ALK-positive large B-cell lymphoma

ALK-positive large B-cell lymphoma (ALK-LBL) was defined by WHO as a neoplasm of ALKpositive monomorphic large immunoblast-like B cells, sometimes with plasmablastic phenotype [67]. These tumors are very rare, representing less than 1% of diffuse large B-cell lymphoma and approximately 60 cases were reported so far. Delsol et al. described this neoplasm in 1997 as morphologically similar to ALCL, although lacking the CD30 expression and T-cell lineage antigens. Although originally the t(2;5) translocation and NPM–ALK fusion gene transcript were not identified in ALK-LBL, further studies showed this alteration and, more commonly, the CLTC–ALK fusion gene [68,69]. Cases with alternative fusion genes (Table 1) and other aberrations were reported subsequently, including SEC31A–ALK [70] and SQSTM1–ALK fusion genes [71], 5´-ALK deletion [72] and duplication of the ALK gene or an additional copy of chromosome 2 [73]. ALK-LBL usually presents with CD138/VS38c/ MUM1 and EMA expression. It frequently has

www.futuremedicine.com

309

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat immunoglobulin gene rearrangement. Pan-leukocyte antigen CD45 is usually weakly expressed and focal in distribution, which, in addition to the frequent lack of CD30, loss of lymphocytespecific antigens (CD3, CD20 and CD79a) and occasional keratin positivity, may lead to misdiagnosis of metastatic carcinoma [73,74]. ALK-LBL usually affects the adults (the peak of incidence occurs in fourth and fifth decade of life), as only 25% of cases were reported in children. There is male predominance (male:female ratio 4:1). It is an aggressive disease, since more than half of patients present with stage III–IV and the overall survival is much lower than that in ALK-positive ALCL and ALK-negative diffuse large B-cell lymphoma. Median and 5-year survival range from 12–24 months and 25–45%, respectively [75,76]. Conventional therapy seems to be less effective than in other types of aggressive non-Hodgkin lymphomas. Despite some evidence from in vitro and animal experiments that ALK inhibitors might be useful in treating ALK-LBL with gene fusions [70,77,78], no data are available on the use of crizotinib in patients with this lymphoma. ●●Inflammatory myofibroblastic tumor

Inflammatory myofibroblastic tumor (IMT) is a rare, low-grade neoplasm belonging to the vaguely defined spectrum of inflammatory pseudotumours. IMT was originally reported as a pulmonary lesion, but subsequent studies showed it may involve other anatomical sites, such as the intestinal mesentery or omentum [79]. The tumor is composed of spindle cell myofibroblasts and inflammatory cells that form a pattern resembling nodular fasciitis or fibrous histiocytoma. The tumor cells show expression of SMA, MSA and vimentin, confirming their myofibroblastic origin [80]. ALK overexpression is observed in about 35–60% of IMT and it usually correlates with the young age of patients [81–83]. The immunohistochemical staining pattern depends on the genetic translocation. TPM3/4–ALK, PPFIBP1–ALK, SEC31L1–ALK and ALK–ATIC fusions resulted in diffuse cytoplasmic staining, CLTC–ALK fusion was associated with granular cytoplasmic staining, while nuclear membrane staining occured in tumors with RanBP2–ALK translocation (Table 1) [4,53,83–88]. The significance of ALK overexpression in IMT for prognostication is based on scarce reports showing better outcome in ALK-positive

310

Future Oncol. (2014) 10(2)

cases [80,89]. In addition, ALK expression allows histological discrimination of IMT from tumors with similar morphological patterns (e.g., spindle cell sarcomas and melanomas, sarcomatoid carcinomas and gastrointestinal stromal tumors) [90]. It is also worth mentioning that targeted therapy using newly developed anti-ALK drugs, such as crizotinib against ALK-positive IMT, showed promising results in the clinical trials [64,91]. ●●Non-small-cell lung carcinoma

Lung cancer is one of the most common types of cancer and is the leading cause of cancer-related deaths worldwide with estimated age worldstandardized incidence rate of 22.9 per 100,000 and 5-year survival rate below 20% [92]. Since the results of treatment are very poor in this group of lesions, identification of any potential molecular treatment target arouses interest of oncologists. In 2007, Soda et al. described ALK translocation into the EML4 gene locus (EML4–ALK ) with an estimated frequency of 6.7% in NSCLCs (five out of 75) [93]. Subsequent reports confirmed this finding, but its incidence ranged from 2.3 to 11.3% [2,94,95]. As a result of this translocation, a chimeric oncogene arises that usually results in ALK overexpression. ALK-positive NSCLCs are usually adenocarcinomas that affect middle-aged never smokers (median age of 52 years). In one study, an increase in incidence of EML4–ALKpositive tumors (to 13% of cases) was achieved by selection of adenocarcinomas depending on presence of at least two features of the following: female sex, Asian ethnicity, never or light smoking history (19 out of 131) [96]. The EML4–ALK fusion gene seems to be mutually exclusive with other aberrations commonly seen in pulmonary adenocarcinomas, such as EGFR and KRAS mutations. Incidence of EML4–ALK alteration is significantly higher in tumors lacking such genetic abnormalities [97]. The breakpoint of the EML4–ALK translocation may vary, as a portion of the ALK gene encoding the tyrosine kinase domain (exons 20–29) may be fused with different coding sequences in the EML4 gene. Recently, a new variant was described with a breakpoint within exon 19 of ALK gene [98]. In addition, other molecular partners of the ALK translocation in NSCLC have been reported, for example KIF5B and KLC1, but their clinical significance is so far unclear (Table 1) [99–101]. Additionally, point mutations in the ALK gene have also been identified that conferred gainof-function to this gene, with a reported incidence

future science group

ALK-positive cancer: still a growing entity  of this mutation of 12.5%. They seemingly confer a growth-stimulating effect for the tumor cells that showed increased proliferation and accumulating tumor weight while transferred to the nude mice [40]. ALK-positive pulmonary adenocarcinomas usually show a solid type of growth and signet ring cytological morphology [102]. Signet ring cells are usually found in the centers of the solid islands of the tumor. In addition, Yoshida et al. identified another growth pattern in ALK-positive pulmonary adenocarcinomas [103]. The tumor presented with cribriform arrangement of growth and showed abundant extracellular mucus. The acinar pattern is also significantly more frequent in the ALK-positive tumors (Figure 2), and these tumors usually have necrotic areas and lymphovascular invasion. The nuclei are usually uniform and rarely is a significant pleomorphism observed. Expression of TTF1 staining is similar in ALKpositive and -negative cancers, whereas the former are more likely p63 positive (72–28%). Coexpression of these two markers was also more common in ALK-positive pulmonary carcinomas and, if it occurred, diffuse reactivity of TTF1 and p63 was observed in the tumor cells. Less commonly, ALK-positive pulmonary adenocarcinomas may show squamous and sarcomatoid component. ALK-positive lung carcinomas are usually more advanced clinically at presentation. Rodig et al. have found only one case of a stage I ALKpositive tumor out of 227 (0.45%) tumors that were amenable for surgical resection, while in a series of higher stage lesions they had 19 out of 131 (14%) cases [104]. It is also worth of noting that EML4–ALK translocation has also been identified in nontumorous tissues collected from patients with

Review

ALK-negative lung carcinoma [2]. However, the exact significance of this observation has been disputed and the results were put into question [105]. Significance of ALK status in NSCLC treatment is well established. Clinical studies evaluating the efficacy of the ALK inhibitor, crizotinib, have shown that it can produce a dramatic improvement in the overall patient status with a complete response rate of 53–57% and a stable disease rate of 26–33% (disease control rate: 79–90%) [106,107]. A retrospective study has proven that crizotinib in ALK-positive patients as a second- or third-line treatment resulted in a 43% increase in 2-year survival rate compared to the other therapies (55 vs 12%, respectively). Additionally, there was no significant survival difference between ALK-positive and -negative cases on standard therapy [108]. Unfortunately, most of the cancers have become resistant to crizotinib within 1 year of treatment. Therefore, several different strategies to overcome the drug resistance are now being investigated. A new generation of ALK inhibitors, such as TAE684 and AP26113, as well as the Hsp90 inhibitor 17-AAG, were highly effective against cells with the gatekeeper mutation L1196M within the kinase domain, which rendered them insensitive to crizotinib [109]. Research conducted in 2012 by Heuckmann et al. on a Ba/F3 cell line model has shown that different variants of the EML4–ALK translocation resulted in different sensitivities to ALK and Hsp90 inhibitors [110]. ●●Neuroblastoma

Neuroblastoma is a poorly differentiated pediatric tumor derived from neural crest cells (neuroblasts) and belongs to the small round blue cell

Figure 2. Non-small-cell lung carcinoma. (A) Well-differentiated pulmonary adenocarcinoma with acinar pattern of growth has strong (B) ALK expression in the cytoplasm of the tumor cells.

future science group

www.futuremedicine.com

311

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat tumor type [111]. Until recently, amplification of the MYCN gene was the most commonly identified molecular alteration in this tumor. Additionally, if present, it usually correlates with aggressive behavior of the tumor. Interestingly, MYCN and ALK share similar chromosomal locus, being located at 2p23–p24 chromosome bands. ALK overexpression was originally reported in 92% of neuroblastoma cases (22 out of 24) [3]. Consecutive studies showed that ALK aberrations in sporadic neuroblastomas include amplifications and point mutations distributed in various exons of the tyrosine kinase domain. However, these structural aberrations involve only 5–25% of neuroblastomas [39,112,113]. Hereditary ALK mutations are now considered to be one of the major causes of familial neuroblastoma. This predisposition is usually a result of missense mutations in the tyrosine kinase domain of ALK. However, unlike ALK, the resequencing of the MYCN coding region from samples taken from tested family members showed no disease-causal sequence variations [114]. In a meta-analysis published in 2010, 6.9% (49 out of 709) of neuroblastomas were found to harbor ALK mutations, with no significant correlation between ALK overexpression and clinical stage (5.7% in International Neuroblastoma Staging System 1, 2, 4S vs 7.5% in International Neuroblastoma Staging System 3 and 4) [115]. However, hotspot mutations at the F1174 position observed in 34.7% of mutated cases were more common in neuroblastomas with MYCN amplification. This alteration seems to confer particularly poor prognosis in this group of neuro­blastomas as only one patient out of ten was alive at the time of observation, while in MYCN-amplified neuroblastoma without the F1174 mutation the 5-year survival rate is 32%. These findings suggest these two aberrations exert a synergistic effect for tumor proliferation and aggressiveness. Likewise, a high level of ALK overexpression caused by chromosome 2p gains was also shown to be associated with poor prognosis. The synergistic effect between ALK and MYCN was further evaluated in a research conducted by Schönherr et al. who have shown that both wild-type and gain-of-function ALK mutations stimulate initiation of MYCN transcription [116]. This may depend on the biological role that ALK plays as a regulator of MYCN transcription. Results of an in vivo murine study published in 2012 also confirmed a functional

312

Future Oncol. (2014) 10(2)

synergy between ALK and MYCN based on increased penetration, enhanced lethality and more rapid onset of neuroblastomas in ALKF1174L/MYCN compound hemizygotes compared to MYCN alone. They also showed reduced apoptosis due to increased expression of antiapoptotic factors (BCL2 and BCLW ) and downregulation of the proapoptotic genes Bak, Bax, Bik, Bid and Noxa [117]. A study using a D. melanogaster mutant construct model showed that the F1774S mutation may result in increased aggressiveness of cancer. The authors also described a patient with neuroblastoma in whom appearance of this mutation in the course of the disease gave rise to rapid deterioration of his clinical status and unresponsiveness to chemotherapy [118]. More research based on similar model systems allowed the separation of ALK mutations in neuroblastoma into three classes – gain-of-function ligand-independent mutations (such as F1774S, F1774L or F1774I), kinase-dead ALK mutants (e.g., I1250T) and ligand-dependent ALK mutations. It was also proven that ALK antagonists, such as crizotinib, may effectively block neurite outgrowth in a ligand-independent manner. They also decreased the activity of all types of mutant ALK receptors, thus inhibiting the ALKdependent signal transduction pathways [119]. The response to the inhibitors depends on the dose and the type of ALK mutation, with F1774L being the most resistant to the drug and with complete regression of the xenograft in cases with ALK amplification or R1275Q mutation [120]. Results of Phase I/II clinical trial of crizotinib efficacy in young patients with relapsed or refractory solid tumors including 34 neuroblastoma cases showed complete response in two patients (5.9%) – one with Arg1275Gln germline ALK mutation and one with unknown ALK status [201]. Eight other patients (23.5%), three with ALK point mutations and five with unknown ALK status, have had a prolonged stable disease ranging from four to at least 39 cycles of therapy, each cycle lasting 28 days [64]. Another ALK inhibitor CH5424802 was shown to block the growth of neuroblastoma cells with F1774L mutation in vitro, but was not tested in vivo so far. The combination of mTOR and ALK inhibition was also effective in treating murine ALK F1774L/MYCN hemizygotes. ALK-targeted therapy may prove useful not only in cases with ALK point mutations, but also in a large number of tumors overexpressing wild-type ALK and

future science group

ALK-positive cancer: still a growing entity  therefore presents a promising new strategy for neuroblastoma treatment [117,121]. ●●Renal cancer

Data on ALK-positive renal cell carcinoma (RCC) are limited thus far. The original reports concerning the occurrence of ALK-positive RCC were case reports. In a series of six pediatric cases of RCC, one had t(2;10)(p23;q22) translocation resulting in VCL–ALK fusion and ALK overexpression, while another showed inv(2) (p23q11.2) inversion in lymph node metastasis but was negative for ALK locus rearrangement. Five specimens, including the ALK positive, developed in African–American patients with sickle cell trait, one from patient of Hispanic descent and without sickle cell trait. The article suggests that ALK aberrations might be the key factor in pathogenesis of ALK-positive RCC [122]. Another case of ALK-positive renal cancer was described with a t(2;10)(p23;q22) translocation. The patient also shared sickle cell trait with the former cases, but histologically it was renal medullary carcinoma (RMC). The authors implied that due to a lack of other treatment options the measurement of ALK oncogenic activation by immunohistochemistry (IHC) and FISH might be a valid diagnostic approach in patients with RMC, providing information about potential sensitivity to ALK inhibitors [123]. Another study revealed ALK expression in nonpediatric RCC [124]. This large-scale screening IHC analysis demonstrated two ALK-positive tumors among 355 renal tumor samples. Both cases were nonclear cell and nonchromophobe RCC with TPM3–ALK and EML4–ALK fusion genes, respectively. Morphologically, one tumor showed a mucinous cribriform pattern that is seemingly a characteristic feature of ALKpositive cancers, as shown in pulmonary carcinoma [103]. The other case was histologically a complex lesion: ALK negative had a clear cell phenotype, whereas ALK-positive component was papillary RCC type 2A. The study confirmed that ALK-positive RCC may occur in adult patients without sickle cell trait. A recent study confirmed the rarity of ALKpositive RCC. Among 534 renal cancers, Sukov et al. revealed two cases with ALK rearrangements in 54 cases with ALK copy number gain as confirmed by FISH [125]. The latter was significantly associated with tumor size, nuclear grade

future science group

Review

and a worse 10-year cancer specific survival in clear cell carcinomas. In conclusion, the exact frequency of ALKpositive RCCs is still uncertain although it seems to more frequently affect specific populations (children and patients with sickle cell trait) and correlate with certain histotypes of RCC (e.g., RMC). The influence of ALK positivity on the the clinical course of RCC remains unclear. Similarly, suitability of ALK targeted therapy in this group of RCC is still an open question. ●●Other tumors with ALK overexpression

In addition to the already mentioned tumors, various ALK aberrations have been described in neoplasms developing at other sites. Two separate studies on Iranian and Chinese patients with esophageal carcinoma using proteomic profiling identified increased TPM4–ALK fusion proteins levels [126,127]. EML4–ALK translocations were detected in colorectal and breast carcinoma by exon array profiling [94]. ALK overexpression in breast cancer was also revealed by IHC. ALK staining was disclosed in 50–100% of evaluated cancer tissues, as well as in normal breast epithelium and other nonepithelial cells [128]. In a recent report, ALK amplification was identified in 75% (nine out of 12) of inflammatory breast cancer (IBC) samples. Further research revealed that crizotinib had caused tumor shrinkage in mouse xenograft IBC and also growth arrest in IBC cell colonies. Based on these data, IBC patients are currently being enrolled to the ongoing Phase I study testing new generation ALK inhibitor LDK378 [129]. Apart from NSCLC and neuroblastoma, point mutations in the ALK gene have been found in anaplastic thyroid carcinoma [43] and medulloblastoma [44], but the biological significance of these mutations has not been evaluated so far. Overexpression of the ALK protein as well as increased levels of the ALK ligand PTN have been identified in glioblastoma samples and cell lines. A reduction of ALK in glioblastoma cells by ribozyme targeting caused decreased phosphorylation of the antiapoptotic protein AKT, which in turn increased apoptosis, reduced tumor growth of xenografts and prolonged survival in athymic nude mice [130]. This effect was further enhanced by simultaneous knockdown of both ALK and PTN [131]. Another experiment on murine xenografts proved that antiALK antibodies decreased the glioblastoma

www.futuremedicine.com

313

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat cell invasiveness by inhibiting PTN-dependent signal transduction [132]. All these results imply that PTN/ALK interaction might be a promising target in glioblastoma therapy. ALK gene amplification was documented in Ewing’s sarcoma/peripheral primitive neuroectodermal tumor, lipoma, lipoblastoma, liposarcoma and retinoblastoma tumor samples based on IHC and a molecular study on 249 cases of soft tissue tumors [133]. Increased number of ALK copies was also found in retinoblastoma and melanoma cell lines [134]. In a recent study ALK immunoreactivity was observed in 94% (30 out of 32) of Merkel cell carcinomas, but the pathoclinical significance of this finding is unclear [135]. Conclusion Tumors with alterations of the ALK gene are heterogenous in terms of morphology and pathological classification. They also run a variable clinical course ranging from indolent to aggressive neoplasm. However, the common molecular alteration may indicate a genetic

marker of potential diagnostic and therapeutic significance. Future perspective We believe that the interest in the role of ALK aberrations in tumorigenesis and the importance of ALK as a target in therapy will remain a hot topic in forthcoming years. The number of tumors recognized to express ALK has been growing rapidly in the last decade and we expect this trend to continue in the future, especially with increasing popularity of new diagnostic techniques, such as exome sequencing, that will enhance our ability to identify ALK-positive tumors. Many clinical trials that will help to establish ALK inhibitors efficacy in patients with ALK-positive tumors are currently ongoing (Table 2). The appearance of new agents could be beneficial for patients who have acquired resistance to crizotinib, as the in vitro and in vivo studies conducted so far show promising results. The ALK-targeted therapy could be a breakthrough in the treatment of some highly malignant tumors such as ALK-LBL, ALK-positive

Table 2. List of currently ongoing interventional studies on ALK-positive tumors. NLM identifier

Drug name

Target

Tumor

Phase

Status

Ref.

NCT01154140 NCT01639001 NCT00932893 NCT00932451 NCT01524926 NCT00939770 NCT01712217 NCT01579994 NCT01822496 NCT01828112 NCT01828099 NCT01685138 NCT01685060 NCT01283516 NCT01634763 NCT01742286 NCT01772797 NCT01871805 NCT01801111 NCT01588028 NCT01284192 NCT01625234 NCT01449461 NCT01562015 NCT01752400

Crizotinib Crizotinib Crizotinib Crizotinib Crizotinib Crizotinib Crizotinib + AT13387 Crizotinib + STA-9090 Crizotinib + erlotinib LDK378 LDK378 LDK378 LDK378 LDK378 LDK378 LDK378 LDK378 + AUY922 RO5424802 RO5424802 RO5424802 ASP3026 X-396 AP26113 Ganetespib AUY922

ALK ALK ALK ALK ALK ALK Hsp90/ALK Hsp90/ALK ALK/EGFR ALK ALK ALK ALK ALK ALK ALK ALK ALK ALK ALK ALK ALK ALK/EGFR Hsp90 Hsp90

ALK NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ tumors ALK+ solid tumors ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ tumors ALK+ tumors ALK+ pediatric tumors ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ NSCLC ALK+ tumors ALK+ solid tumors ALK+ or EGFR+ tumors ALK+ NSCLC ALK+ NSCLC

III III III II II I/II I/II I/II I/II III III II II I I I Ib I/II I/II I/II I I I/II II II

R R O R R R R R N N N R R R R N N N R R R R R R R

[202]

+

[203] [204] [205] [206] [201] [207] [208] [209] [210] [211] [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] [222] [223] [224] [225]

ALK+: ALK positive; EGFR+: EGFR positive; N: Not yet recruiting; NSCLC: Non-small-cell lung carcinoma; O: Ongoing, not recruiting; R: Currently recruiting.

314

Future Oncol. (2014) 10(2)

future science group

ALK-positive cancer: still a growing entity 

Review

EXECUTIVE SUMMARY ALK structure & function ●●

ALK is a receptor tyrosine kinase belonging to the insulin receptor superfamily.

●●

ALK plays a role in neurogenesis and cognitive process, and is expressed by normal human tissues of the CNS.

Intracellular function ●●

ALK activates several downstream signaling pathways, such as PI3K, MAPK, PLCg and STAT3.

●●

Human ligands of ALK include PTN and midkine.

ALK activation in cancer ●●

Translocations, amplifications and point mutations of ALK locus can induce tumorigenesis.

ALK-positive anaplastic large-cell lymphoma ●●

ALK translocations can be found in 50–60% of anaplastic large-cell lymphomas (ALCLs). The most frequent is t(2;5)(p23;p25), which results in expression of the NPM–ALK fusion protein.

●●

ALK-positive ALCL has better prognosis than ALK-negative ALCL, which might be a result of increased expression of proapoptotic proteins.

ALK-positive large B-cell lymphoma ●●

ALK-large B-cell lymphoma is a rare tumor representing less than 1% of diffuse large B-cell lymphoma with worse prognosis than ALCL.

●●

In vitro and animal studies have showed that ALK inhibitors could be effective in the treatment of ALK-large B-cell lymphoma, but there were no clinical trials so far.

Inflammatory myofibroblastic tumor ●●

ALK overexpression can be found in 35–60% of these low-grade tumors and can help to discriminate them from more malignant tumors.

●●

ALK inhibitors show promising results in clinical trials.

Non-small-cell lung carcinoma ●●

ALK translocations can be found in 2–11% of non-small-cell lung cancer and are more common in middle-aged patients with adenocarcinoma without EGFR or KRAS mutations.

●●

Two typical histological patterns were described – the cribriform pattern and the solid pattern with signet ring cells.

●●

Crizotinib, an ALK inhibitor, can cause a dramatic improvement in 2-year survival, but drug resistance increases rapidly in the course of treatment.

●●

New generation ALK inhibitors able to overcome the crizotinib resistance are currently in development.

Neuroblastoma ●●

ALK overexpression is found in 92% of neuroblastomas, whereas structural aberrations involve 5–25% of these tumors.

●●

Hereditary ALK mutations are believed to be one of the major causes of familial neuroblastoma.

●●

Hotspot ALK mutations at the F1174 position are more frequent in neuroblastomas with MYCN amplification and are associated with poor prognosis.

Renal cancer ●●

ALK translocations were found in less than 1% of renal cell carcinoma cases and are probably more frequent in children and patients with sickle cell trait.

Other tumors with ALK overexpression ●●

ALK aberrations were also found in breast carcinoma, esophageal carcinoma, anaplastic thyroid carcinoma, medulloblastoma, glioblastoma, Ewing’s sarcoma, retinoblastoma, lipoma, lipoblastoma, liposarcoma and also in melanoma cell lines.

future science group

www.futuremedicine.com

315

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat RCC, neuroblastoma or even glioblastoma, thus giving a new hope for patients with an otherwise dramatically poor prognosis. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a

References Papers of special note have been highlighted as: of interest of considerable interest l

l l

1

l l

2

Morris SW, Kirstein MN, Valentine MB et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science 263(5151), 1281–1284 (1994). First description of ALK translocation in cancer. Martelli MP, Sozzi G, Hernandez L et al. EML4–ALK rearrangement in non-small cell lung cancer and non-tumor lung tissues. Am. J. Pathol. 174(2), 661–670 (2009).

3

Lamant L, Pulford K, Bischof D et al. Expression of the ALK tyrosine kinase gene in neuroblastoma. Am. J. Pathol. 156(5), 1711–1721 (2000).

4

Lawrence B, Perez-Atayde A, Hibbard MK et al. TPM3–ALK and TPM4–ALK oncogenes in inflammatory myofibroblastic tumors. Am. J. Pathol. 157(2), 377–384 (2000).

5

6

7

8

9

316

Morris SW, Naeve C, Mathew P et al. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin’s lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK). Oncogene 14(18), 2175–2188 (1997). Iwahara T, Fujimoto J, Wen D et al. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. Oncogene 14(4), 439–449 (1997). Bilsland JG, Wheeldon A, Mead A et al. Behavioral and neurochemical alterations in mice deficient in anaplastic lymphoma kinase suggest therapeutic potential for psychiatric indications. Neuropsychopharmacology 33(3), 685–700 (2008). Pulford K, Lamant L, Morris SW et al. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood 89(4), 1394–1404 (1997). Rohrbough J, Kent KS, Broadie K, Weiss JB. jelly belly trans-synaptic signaling to

financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert t­estimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

anaplastic lymphoma kinase regulates neurotransmission strength and synapse architecture. Dev. Neurobiol. 73(3), 189–208 (2013). 10 Stoica GE, Kuo A, Aigner A et al.

Identification of anaplastic lymphoma kinase as a receptor for the growth factor pleiotrophin. J. Biol. Chem. 276(20), 16772–16779 (2001). 11 Stoica GE, Kuo A, Powers C et al. Midkine

binds to anaplastic lymphoma kinase (ALK) and acts as a growth factor for different cell types. J. Biol. Chem. 277(39), 35990–35998 (2002). 12 Bai RY, Dieter P, Peschel C, Morris SW,

Duyster J. Nucleophosmin-anaplastic lymphoma kinase of large-cell anaplastic lymphoma is a constitutively active tyrosine kinase that utilizes phospholipase C-gamma to mediate its mitogenicity. Mol. Cell. Biol. 18(12), 6951–6961 (1998). 13 Noh DY, Shin SH, Rhee SG.

Phosphoinositide-specific phospholipase C and mitogenic signaling. Biochim. Biophys. Acta 1242(2), 99–113 (1995). 14 Riera L, Lasorsa E, Ambrogio C, Surrenti N,

Voena C, Chiarle R. Involvement of Grb2 adaptor protein in nucleophosmin-anaplastic lymphoma kinase (NPM–ALK)-mediated signaling and anaplastic large cell lymphoma growth. J. Biol. Chem. 285(34), 26441–26450 (2010). 15 Kinney MC, Higgins RA, Medina EA.

Anaplastic large cell lymphoma: twenty-five years of discovery. Arch. Pathol. Lab. Med. 135(1), 19–43 (2011). 16 Steelman LS, Franklin RA, Abrams SL et al.

Roles of the Ras/Raf/MEK/ERK pathway in leukemia therapy. Leukemia 25(7), 1080–1094 (2011). 17 Abrams SL, Steelman LS, Shelton JG et al.

The Raf/MEK/ERK pathway can govern drug resistance, apoptosis and sensitivity to targeted therapy. Cell Cycle 9(9), 1781–1791 (2010). 18 Lopiccolo J, Blumenthal GM, Bernstein WB,

Dennis PA. Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist. Updat. 11(1–2), 32–50 (2008).

Future Oncol. (2014) 10(2)

19 Bai RY, Ouyang T, Miething C, Morris SW,

Peschel C, Duyster J. Nucleophosminanaplastic lymphoma kinase associated with anaplastic large-cell lymphoma activates the phosphatidylinositol 3-kinase/Akt antiapoptotic signaling pathway. Blood 96(13), 4319–4327 (2000). 20 Cardone MH, Roy N, Stennicke HR et al.

Regulation of cell death protease caspase-9 by phosphorylation. Science 282(5392), 1318–1321 (1998). 21 Rassidakis GZ, Feretzaki M, Atwell C et al.

Inhibition of Akt increases p27Kip1 levels and induces cell cycle arrest in anaplastic large cell lymphoma. Blood 105(2), 827–829 (2005). 22 Marzec M, Kasprzycka M, Liu X, Raghunath

PN, Wlodarski P, Wasik MA. Oncogenic tyrosine kinase NPM/ALK induces activation of the MEK/ERK signaling pathway independently of c-Raf. Oncogene 26(6), 813–821 (2007). 23 Singh RR, Cho-Vega JH, Davuluri Y et al.

Sonic hedgehog signaling pathway is activated in ALK-positive anaplastic large cell lymphoma. Cancer Res. 69(6), 2550–2558 (2009). 24 Groner B, Lucks P, Borghouts C. The

function of Stat3 in tumor cells and their microenvironment. Semin. Cell Dev. Biol. 19(4), 341–350 (2008). 25 Al Zaid Siddiquee K, Turkson J. STAT3 as a

target for inducing apoptosis in solid and hematological tumors. Cell Res. 18(2), 254–267 (2008). 26 Amin HM, Medeiros LJ, Ma Y et al.

Inhibition of JAK3 induces apoptosis and decreases anaplastic lymphoma kinase activity in anaplastic large cell lymphoma. Oncogene 22(35), 5399–5407 (2003). 27 Amin HM, Mcdonnell TJ, Ma Y et al.

Selective inhibition of STAT3 induces apoptosis and G(1) cell cycle arrest in ALK-positive anaplastic large cell lymphoma. Oncogene 23(32), 5426–5434 (2004). 28 Lai R, Rassidakis GZ, Lin Q, Atwell C,

Medeiros LJ, Amin HM. Jak3 activation is significantly associated with ALK expression in anaplastic large cell lymphoma. Hum. Pathol. 36(9), 939–944 (2005).

future science group

ALK-positive cancer: still a growing entity  29 Qiu L, Lai R, Lin Q et al. Autocrine release

of interleukin-9 promotes Jak3-dependent survival of ALK+ anaplastic large-cell lymphoma cells. Blood 108(7), 2407–2415 (2006). 30 Haura EB, Zheng Z, Song L, Cantor A,

Bepler G. Activated epidermal growth factor receptor-Stat-3 signaling promotes tumor survival in vivo in non-small cell lung cancer. Clin. Cancer Res. 11(23), 8288–8294 (2005). 31 Pearson JD, Lee JK, Bacani JT, Lai R,

Ingham RJ. NPM–ALK: The prototypic member of a family of oncogenic fusion tyrosine kinases. J. Signal. Transduct. 123253 (2012). l l

Extensive review discussing the molecular basis of the effect of ALK translocations on proliferation and cell survival in cancer.

32 Zhu H, Vishwamitra D, Curry CV et al.

NPM–ALK up-regulates iNOS expression through a STAT3/microRNA-26adependent mechanism. J. Pathol. 230(1), 82–94 (2013). 33 Zhang Q, Wang HY, Liu X, Wasik MA.

STAT5A is epigenetically silenced by the tyrosine kinase NPM1-ALK and acts as a tumor suppressor by reciprocally inhibiting NPM1-ALK expression. Nat. Med. 13(11), 1341–1348 (2007). 34 Han Y, Amin HM, Franko B, Frantz C, Shi

X, Lai R. Loss of SHP1 enhances JAK3/STAT3 signaling and decreases proteosome degradation of JAK3 and NPM–ALK in ALK+ anaplastic large-cell lymphoma. Blood 108(8), 2796–2803 (2006). 35 Cussac D, Greenland C, Roche S et al.

Nucleophosmin-anaplastic lymphoma kinase of anaplastic large-cell lymphoma recruits, activates, and uses pp60c-src to mediate its mitogenicity. Blood 103(4), 1464–1471 (2004). 36 Shi P, Lai R, Lin Q et al. IGF-IR tyrosine

kinase interacts with NPM–ALK oncogene to induce survival of T-cell ALK+ anaplastic large-cell lymphoma cells. Blood 114(2), 360–370 (2009). 37 Shi B, Vishwamitra D, Granda JG, Whitton

T, Shi P, Amin HM. Molecular and functional characterizations of the association and interactions between nucleophosmin-anaplastic lymphoma kinase and type I insulin-like growth factor receptor. Neoplasia 15(6), 669–683 (2013). 38 Turner SD, Alexander DR. What have we

learnt from mouse models of NPM–ALKinduced lymphomagenesis? Leukemia 19(7), 1128–1134 (2005).

future science group

39 Caren H, Abel F, Kogner P, Martinsson T.

High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours. Biochem. J. 416(2), 153–159 (2008). 40 Wang YW, Tu PH, Lin KT, Lin SC, Ko JY,

Jou YS. Identification of oncogenic point mutations and hyperphosphorylation of anaplastic lymphoma kinase in lung cancer. Neoplasia 13(8), 704–715 (2011). 41 Vishwamitra D, Li Y, Wilson D et al.

MicroRNA 96 is a post-transcriptional suppressor of anaplastic lymphoma kinase expression. Am. J. Pathol. 180(5), 1772–1780 (2012). 42 Bonvini P, Dalla Rosa H, Vignes N, Rosolen

A. Ubiquitination and proteasomal degradation of nucleophosmin-anaplastic lymphoma kinase induced by 17-allylaminodemethoxygeldanamycin: role of the cochaperone carboxyl heat shock protein 70-interacting protein. Cancer Res. 64(9), 3256–3264 (2004). 43 Murugan AK, Xing M. Anaplastic thyroid

cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 71(13), 4403–4411 (2011). 44 Coco S, De Mariano M, Valdora F et al.

Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma. J. Hum. Genet. 57(10), 682–684 (2012). 45 Stein H, Mason DY, Gerdes J et al. The

expression of the Hodgkin’s disease associated antigen Ki-1 in reactive and neoplastic lymphoid tissue: evidence that ReedSternberg cells and histiocytic malignancies are derived from activated lymphoid cells. Blood 66(4), 848–858 (1985). 46 Kaneko Y, Frizzera G, Edamura S et al. A

novel translocation, t(2;5)(p23;q35), in childhood phagocytic large T-cell lymphoma mimicking malignant histiocytosis. Blood 73(3), 806–813 (1989). 47 Lamant L, Dastugue N, Pulford K, Delsol G,

Mariame B. A new fusion gene TPM3–ALK in anaplastic large cell lymphoma created by a (1;2)(q25;p23) translocation. Blood 93(9), 3088–3095 (1999). 48 Meech SJ, Mcgavran L, Odom LF et al.

Unusual childhood extramedullary hematologic malignancy with natural killer cell properties that contains tropomyosin 4 – anaplastic lymphoma kinase gene fusion. Blood 98(4), 1209–1216 (2001). 49 Hernandez L, Bea S, Bellosillo B et al.

Diversity of genomic breakpoints in TFG–ALK translocations in anaplastic large cell lymphomas: identification of a new

Review

TFG–ALK(XL) chimeric gene with transforming activity. Am. J. Pathol. 160(4), 1487–1494 (2002). 50 Colleoni GW, Bridge JA, Garicochea B, Liu

J, Filippa DA, Ladanyi M. ATIC-ALK: a novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35). Am. J. Pathol. 156(3), 781–789 (2000). 51 Touriol C, Greenland C, Lamant L et al.

Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like). Blood 95(10), 3204–3207 (2000). 52 Tort F, Pinyol M, Pulford K et al. Molecular

characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. Lab. Invest. 81(3), 419–426 (2001). 53 Cools J, Wlodarska I, Somers R et al.

Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 34(4), 354–362 (2002). 54 Lamant L, Gascoyne RD, Duplantier MM

et al. Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma. Genes Chromosomes Cancer 37(4), 427–432 (2003). 55 Falini B, Pileri S, Zinzani PL et al. ALK+

lymphoma: clinico-pathological findings and outcome. Blood 93(8), 2697–2706 (1999). 56 Delsol G, Jaffe ES, Falini B. Anaplastic large

cell lymphoma (ALCL), ALK-positive. In: WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Swerdlow S, Campo E, Harris NL (Eds). IARC, Lyon, France, 312–316 (2008). 57 Mason D, Harris NL, Delsol G. Anaplastic

large cell lymphoma, ALK-negative. In: WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Swerdlow S, Campo E, Harris NL (Eds). IARC, Lyon, France, 317–319 (2008). 58 Lamant L, De Reynies A, Duplantier MM

et al. Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. Blood 109(5), 2156–2164 (2007). 59 Vose J, Armitage J, Weisenburger D.

International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J. Clin. Oncol. 26(25), 4124–4130 (2008).

www.futuremedicine.com

317

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat 60 Gascoyne RD, Aoun P, Wu D et al.

Prognostic significance of anaplastic lymphoma kinase (ALK) protein expression in adults with anaplastic large cell lymphoma. Blood 93(11), 3913–3921 (1999).

69 Onciu M, Behm FG, Downing JR et al.

ALK-positive plasmablastic B-cell lymphoma with expression of the NPM–ALK fusion transcript: report of 2 cases. Blood 102(7), 2642–2644 (2003). 70 Van Roosbroeck K, Cools J, Dierickx D

61 Savage KJ, Harris NL, Vose JM et al. ALK-

anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111(12), 5496–5504 (2008).

et al. ALK-positive large B-cell lymphomas with cryptic SEC31A–ALK and NPM1-ALK fusions. Haematologica 95(3), 509–513 (2010). 71 Takeuchi K, Soda M, Togashi Y et al.

Identification of a novel fusion, SQSTM1–ALK, in ALK-positive large B-cell lymphoma. Haematologica 96(3), 464–467 (2011).

62 Yu R, Chen G, Zhou C et al. Extra copies of

ALK gene locus is a recurrent genetic aberration and favorable prognostic factor in both ALK-positive and ALK-negative anaplastic large cell lymphomas. Leuk. Res. 36(9), 1141–1146 (2012). 63 Ten Berge RL, Meijer CJ, Dukers DF et al.

Expression levels of apoptosis-related proteins predict clinical outcome in anaplastic large cell lymphoma. Blood 99(12), 4540–4546 (2002). l

Provides valuable information on the proapoptotic effect of ALK expression, which might explain the better prognosis in ALK-positive anaplastic large-cell lymphoma.

72 Lee HW, Kim K, Kim W, Ko YH. ALK-

positive diffuse large B-cell lymphoma: report of three cases. Hematol. Oncol. 26(2), 108–113 (2008). 73 Beltran B, Castillo J, Salas R et al.

ALK-positive diffuse large B-cell lymphoma: report of four cases and review of the literature. J. Hematol. Oncol. 2, 11 (2009). 74 Morgan EA, Nascimento AF. Anaplastic

lymphoma kinase-positive large B-cell lymphoma: an underrecognized aggressive lymphoma. Adv. Hematol. 2012, 529572 (2012). 75 Ott G, Ziepert M, Klapper W et al.

Immunoblastic morphology but not the immunohistochemical GCB/nonGCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. Blood 116(23), 4916–4925 (2010).

64 Mosse YP, Lim MS, Voss SD et al. Safety

l l

and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group Phase 1 consortium study. Lancet Oncol. 14(6), 472–480 (2013).

76 Alizadeh AA, Eisen MB, Davis RE et al.

Most recent report on the efficacy of crizotinib in ALK-positive anaplastic large-cell lymphoma, inflammatory myofibroblastic tumor and neuroblastoma.

Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403(6769), 503–511 (2000).

65 Gambacorti-Passerini C, Messa C, Pogliani

77 Cerchietti L, Damm-Welk C, Vater I et al.

Inhibition of anaplastic lymphoma kinase (ALK) activity provides a therapeutic approach for CLTC–ALK-positive human diffuse large B cell lymphomas. PLoS One 6(4), e18436 (2011).

EM. Crizotinib in anaplastic large-cell lymphoma. N. Engl. J. Med. 364(8), 775–776 (2011). 66 Foyil KV, Bartlett NL. Brentuximab vedotin

and crizotinib in anaplastic large-cell lymphoma. Cancer J. 18(5), 450–456 (2012). 67 Delsol G, Campo E, Gascoyne R. ALK-

positive large B-cell lymphoma. In: WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Swerdlow S, Campo E, Harris NL (Eds). IARC, Lyon, France, 244–245 (2008). 68 De Paepe P, Baens M, Van Krieken H et al.

ALK activation by the CLTC–ALK fusion is a recurrent event in large B-cell lymphoma. Blood 102(7), 2638–2641 (2003).

318

l

Demonstrates that ALK inhibitors may potentially be used in the therapy of ALK-positive diffuse large B-cell lymphoma based on in vitro and in vivo studies.

78 Galkin AV, Melnick JS, Kim S et al.

Identification of NVP-TAE684, a potent, selective, and efficacious inhibitor of NPM–ALK. Proc. Natl Acad. Sci. USA 104(1), 270–275 (2007). 79 Janik JS, Janik JP, Lovell MA, Hendrickson

RJ, Bensard DD, Greffe BS. Recurrent

Future Oncol. (2014) 10(2)

inflammatory pseudotumors in children. J. Pediatr. Surg. 38(10), 1491–1495 (2003). 80 Coffin CM, Hornick JL, Fletcher CD.

Inflammatory myofibroblastic tumor: comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am. J. Surg. Pathol. 31(4), 509–520 (2007). 81 Coffin CM, Patel A, Perkins S,

Elenitoba-Johnson KS, Perlman E, Griffin CA. ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod. Pathol. 14(6), 569–576 (2001). 82 Griffin CA, Hawkins AL, Dvorak C,

Henkle C, Ellingham T, Perlman EJ. Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res. 59(12), 2776–2780 (1999). 83 Cook JR, Dehner LP, Collins MH et al.

Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: a comparative immunohistochemical study. Am. J. Surg. Pathol. 25(11), 1364–1371 (2001). 84 Bridge JA, Kanamori M, Ma Z et al. Fusion

of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. Am. J. Pathol. 159(2), 411–415 (2001). 85 Debiec-Rychter M, Marynen P, Hagemeijer

A, Pauwels P. ALK–ATIC fusion in urinary bladder inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 38(2), 187–190 (2003). 86 Ma Z, Hill DA, Collins MH et al. Fusion of

ALK to the Ran-binding protein 2 (R ANBP2) gene in inflammatory myofibroblastic tumor. Genes Chromosomes Cancer 37(1), 98–105 (2003). 87 Takeuchi K, Soda M, Togashi Y et al.

Pulmonary inflammatory myofibroblastic tumor expressing a novel fusion, PPFIBP1–ALK: reappraisal of anti-ALK immunohistochemistry as a tool for novel ALK fusion identification. Clin. Cancer Res. 17(10), 3341–3348 (2011). 88 Panagopoulos I, Nilsson T, Domanski HA

et al. Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor. Int. J. Cancer. 118(5), 1181–1186 (2006). 89 Chun YS, Wang L, Nascimento AG, Moir

CR, Rodeberg DA. Pediatric inflammatory myofibroblastic tumor: anaplastic lymphoma kinase (ALK) expression and prognosis. Pediatr. Blood Cancer 45(6), 796–801 (2005).

future science group

ALK-positive cancer: still a growing entity  90 Fuehrer NE, Keeney GL, Ketterling RP,

Knudson RA, Bell DA. ALK-1 protein expression and ALK gene rearrangements aid in the diagnosis of inflammatory myofibroblastic tumors of the female genital tract. Arch. Pathol. Lab. Med. 136(6), 623–626 (2012).

analysis and immunohistochemistry is useful for screening of EML4–ALK-positive lung adenocarcinoma. J. Clin. Pathol. 63(12), 1066–1070 (2010). l

91 Butrynski JE, D’adamo DR, Hornick JL et al.

Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor. N. Engl. J. Med. 363(18), 1727–1733 (2010).

103 Yoshida A, Tsuta K, Nakamura H et al.

Comprehensive histologic analysis of ALKrearranged lung carcinomas. Am. J. Surg. Pathol. 35(8), 1226–1234 (2011).

92 Siegel R, Naishadham D, Jemal A. Cancer

statistics, 2012. CA Cancer J. Clin. 62(1), 10–29 (2012).

l

93 Soda M, Choi YL, Enomoto M et al.

Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature 448(7153), 561–566 (2007).

95 Takahashi T, Sonobe M, Kobayashi M et al.

Clinicopathologic features of non-small-cell lung cancer with EML4–ALK fusion gene. Ann. Surg. Oncol. 17(3), 889–897 (2010).

Unique clinicopathologic features characterize ALK-rearranged lung adenocarcinoma in the western population. Clin. Cancer Res. 15(16), 5216–5223 (2009). 105 Mano H, Takeuchi K. EML4–ALK fusion in

lung. Am. J. Pathol. 176(3), 1552–1553; author reply 1553–1554 (2010). 106 Kwak EL, Bang YJ, Camidge DR et al.

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363(18), 1693–1703 (2010).

96 Shaw AT, Yeap BY, Mino-Kenudson M et al.

Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4–ALK. J. Clin. Oncol. 27(26), 4247–4253 (2009). 97 Zhang X, Zhang S, Yang X et al. Fusion of

EML4 and ALK is associated with development of lung adenocarcinomas lacking EGFR and KRAS mutations and is correlated with ALK expression. Mol. Cancer 9, 188 (2010).

107 Hallberg B, Palmer RH. ALK and NSCLC:

targeted therapy with ALK inhibitors. F1000 Med. Rep. 3, 21 (2011). 108 Shaw AT, Yeap BY, Solomon BJ et al. Effect

of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: a retrospective analysis. Lancet Oncol. 12(11), 1004–1012 (2011).

98 Penzel R, Schirmacher P, Warth A. A novel

EML4–ALK variant: exon 6 of EML4 fused to exon 19 of ALK. J. Thorac. Oncol. 7(7), 1198–1199 (2012). 99 Takeuchi K, Choi YL, Togashi Y et al. KIF5B-

ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer. Clin. Cancer Res. 15(9), 3143–3149 (2009). 100 Jung Y, Kim P, Keum J et al. Discovery of

ALK–PTPN3 gene fusion from human non‑small cell lung carcinoma cell line using next generation RNA sequencing. Genes Chromosomes Cancer 51(6), 590–597 (2012). 101 Togashi Y, Soda M, Sakata S et al. KLC1–

ALK: a novel fusion in lung cancer identified using a formalin-fixed paraffin-embedded tissue only. PLoS One 7(2), e31323 (2012). 102 Jokoji R, Yamasaki T, Minami S et al.

Combination of morphological feature

future science group

Describes the distinct histology of ALK-positive non-small-cell lung cancer, which can be used in the microscopic identification of these tumors.

104 Rodig SJ, Mino-Kenudson M, Dacic S et al.

94 Lin E, Li L, Guan Y et al. Exon array profiling

detects EML4–ALK fusion in breast, colorectal, and non-small cell lung cancers. Mol. Cancer Res. 7(9), 1466–1476 (2009).

Describes the distinct histology of ALK-positive non-small-cell lung cancer, which can be used in the microscopic identification of these tumors.

l l

Report on the effects of crizotinib therapy on overall survival in ALK-positive non-small-cell lung cancer patients.

109 Katayama R, Khan TM, Benes C et al.

Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4–ALK. Proc. Natl Acad. Sci. USA 108(18), 7535–7540 (2011). 110 Heuckmann JM, Balke-Want H, Malchers F

et al. Differential protein stability and ALK inhibitor sensitivity of EML4–ALK fusion variants. Clin. Cancer Res. 18(17), 4682–4690 (2012). 111 Maris JM, Hogarty MD, Bagatell R, Cohn

SL. Neuroblastoma. Lancet 369(9579), 2106–2120 (2007). 112 Osajima-Hakomori Y, Miyake I, Ohira M,

Nakagawara A, Nakagawa A, Sakai R.

Review

Biological role of anaplastic lymphoma kinase in neuroblastoma. Am. J. Pathol. 167(1), 213–222 (2005). 113 Janoueix-Lerosey I, Lequin D, Brugieres L

et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455(7215), 967–970 (2008). 114 Mosse YP, Laudenslager M, Longo L et al.

Identification of ALK as a major familial neuroblastoma predisposition gene. Nature 455(7215), 930–935 (2008). 115 De Brouwer S, De Preter K, Kumps C et al.

Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin. Cancer Res. 16(17), 4353–4362 (2010). 116 Schönherr C, Ruuth K, Kamaraj S et al.

Anaplastic lymphoma kinase (ALK) regulates initiation of transcription of MYCN in neuroblastoma cells. Oncogene 31(50), 5193–5200 (2012). 117 Berry T, Luther W, Bhatnagar N et al. The

ALK(F1174L) mutation potentiates the oncogenic activity of MYCN in neuroblastoma. Cancer Cell 22(1), 117–130 (2012). 118 Martinsson T, Eriksson T, Abrahamsson J

et al. Appearance of the novel activating F1174S ALK mutation in neuroblastoma correlates with aggressive tumor progression and unresponsiveness to therapy. Cancer Res. 71(1), 98–105 (2011). 119 Chand D, Yamazaki Y, Ruuth K et al. Cell

culture and Drosophila model systems define three classes of anaplastic lymphoma kinase mutations in neuroblastoma. Dis. Model. Mech. 6(2), 373–382 (2013). 120 Bresler SC, Wood AC, Haglund EA et al.

Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma. Sci. Transl. Med. 3(108), 108ra114 (2011). 121 Matthay KK, George RE, Yu AL. Promising

therapeutic targets in neuroblastoma. Clin. Cancer Res. 18(10), 2740–2753 (2012). 122 Debelenko LV, Raimondi SC, Daw N et al.

Renal cell carcinoma with novel VCL–ALK fusion: new representative of ALK-associated tumor spectrum. Mod. Pathol. 24(3), 430–442 (2011). 123 Marino-Enriquez A, Ou WB, Weldon CB,

Fletcher JA, Perez-Atayde AR. ALK rearrangement in sickle cell trait-associated renal medullary carcinoma. Genes Chromosomes Cancer 50(3), 146–153 (2011). 124 Sugawara E, Togashi Y, Kuroda N et al.

Identification of anaplastic lymphoma kinase

www.futuremedicine.com

319

Review  Gorczyński, Prełowska, Adam, Czapiewski & Biernat fusions in renal cancer: large-scale immunohistochemical screening by the intercalated antibody-enhanced polymer method. Cancer 118(18), 4427–4436 (2012). 125 Sukov WR, Hodge JC, Lohse CM et al. ALK

alterations in adult renal cell carcinoma: frequency, clinicopathologic features and outcome in a large series of consecutively treated patients. Mod. Pathol. 25(11), 1516–1525 (2012). l

Most recent large-scale study on the clinical significance of ALK aberrations in renal cell carcinoma.

126 Du XL, Hu H, Lin DC et al. Proteomic

profiling of proteins dysregulted in Chinese esophageal squamous cell carcinoma. J. Mol. Med. (Berl.) 85(8), 863–875 (2007). 127 Jazii FR, Najafi Z, Malekzadeh R et al.

Identification of squamous cell carcinoma associated proteins by proteomics and loss of beta tropomyosin expression in esophageal cancer. World J. Gastroenterol. 12(44), 7104–7112 (2006). 128 Perez-Pinera P, Chang Y, Astudillo A,

Mortimer J, Deuel TF. Anaplastic lymphoma kinase is expressed in different subtypes of human breast cancer. Biochem. Biophys. Res. Commun. 358(2), 399–403 (2007). 129 Tuma RS. ALK gene amplified in most

inflammatory breast cancers. J. Natl Cancer Inst. 104(2), 87–88 (2012). 130 Powers C, Aigner A, Stoica GE, Mcdonnell

K, Wellstein A. Pleiotrophin signaling through anaplastic lymphoma kinase is rate-limiting for glioblastoma growth. J. Biol. Chem. 277(16), 14153–14158 (2002).

135 Filtenborg-Barnkob BE, Bzorek M.

Expression of anaplastic lymphoma kinase in Merkel cell carcinomas. Hum. Pathol. 44(8), 1656–1664 (2013). ●●Websites 201 ClinicalTrials.gov. Crizotinib in treating

young patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma. http://clinicaltrials.gov/show/ NCT00939770 (Accessed 24 July 2013) 202 ClinicalTrials.gov. A clinical trial testing the

efficacy of crizotinib versus standard chemotherapy pemetrexed plus cisplatin or carboplatin in patients with ALK positive non squamous cancer of the lung (PROFILE 1014). http://clinicaltrials.gov/show/NCT01154140 (Accessed 24 July 2013) 203 ClinicalTrials.gov. A study of crizotinib

versus chemotherapy in previously untreated alk positive east asian non-small cell lung cancer patients. http://clinicaltrials.gov/show/NCT01639001 (Accessed 24 July 2013) 204 ClinicalTrials.gov. An investigational drug,

PF-02341066 is being studied versus standard of care in patients with advanced non-small cell lung cancer with a specific gene profile involving the anaplastic lymphoma kinase (ALK) gene. http://clinicaltrials.gov/show/ NCT00932893 (Accessed 24 July 2013) 205 ClinicalTrials.gov. An investigational drug,

Czubayko F, Lamszus K, Aigner A. Enhanced antitumorigenic effects in glioblastoma on double targeting of pleiotrophin and its receptor ALK. Neoplasia 11(2), 145–156 (2009).

PF-02341066, is being studied in patients with advanced non-small cell lung cancer with a specific gene profile involving the anaplastic lymphoma kinase (ALK) gene. http://clinicaltrials.gov/show/NCT00932451 (Accessed 24 July 2013)

132 Stylianou DC, Auf Der Maur A, Kodack DP

206 ClinicalTrials.gov. CREATE. Cross-tumoral

131 Grzelinski M, Steinberg F, Martens T,

et al. Effect of single-chain antibody targeting of the ligand-binding domain in the anaplastic lymphoma kinase receptor. Oncogene 28(37), 3296–3306 (2009). 133 Li XQ, Hisaoka M, Shi DR, Zhu XZ,

Hashimoto H. Expression of anaplastic lymphoma kinase in soft tissue tumors: an immunohistochemical and molecular study of 249 cases. Hum. Pathol. 35(6), 711–721 (2004). 134 Dirks WG, Fahnrich S, Lis Y, Becker E,

Macleod RA, Drexler HG. Expression and functional analysis of the anaplastic lymphoma kinase (ALK) gene in tumor cell lines. Int. J. Cancer 100(1), 49–56 (2002).

320

Phase 2 with crizotinib. http://clinicaltrials.gov/show/NCT01524926 (Accessed 24 July 2013) 207 ClinicalTrials.gov. A study of AT13387 in

patients with non-small cell lung cancer (NSCLC) alone and in combination with crizotinib. http://clinicaltrials.gov/show/NCT01712217 (Accessed 24 July 2013) 208 ClinicalTrials.gov. Crizotinib and STA-9090

in ALK positive lung cancers. http://clinicaltrials.gov/show/NCT01579994 (Accessed July 2013) 209 ClinicalTrials.gov. Erlotinib hydrochloride or

crizotinib and chemoradiation therapy in

Future Oncol. (2014) 10(2)

treating patients with stage III non-small cell lung cancer. http://clinicaltrials.gov/show/ NCT01822496 (Accessed 24 July 2013) 210 ClinicalTrials.gov. LDK378 versus

chemotherapy in ALK rearranged (ALK Positive) patients previously treated with chemotherapy (platinum doublet) and crizotinib. http://clinicaltrials.gov/show/ NCT01828112 (Accessed 24 July 2013) 211 ClinicalTrials.gov. LDK378 versus

chemotherapy in previously untreated patients with ALK rearranged non-small cell lung cancer. http://clinicaltrials.gov/show/ NCT01828099 (Accessed 24 July 2013) 212 ClinicalTrials.gov. LDK378 in Crizotinib

naive adult patients with ALK-activated non-small cell lung cancer. http://clinicaltrials.gov/show/ NCT01685138 (Accessed 24 July 2013) 213 ClinicalTrials.gov. LDK378 in adult patients

with ALK-activated NSCLC previously treated with chemotherapy and crizotinib. http://clinicaltrials.gov/show/ NCT01685060 (Accessed 24 July 2013) 214 ClinicalTrials.gov. A dose finding study with

oral LDK378 in patients with tumors characterized by genetic abnormalities in anaplastic lymphoma kinase (ALK). http://clinicaltrials.gov/show/ NCT01283516 (Accessed 24 July 2013) 215 ClinicalTrials.gov. Study of safety and

preliminary efficacy for LDK378 in Japanese patients with genetic alterations in anaplastic lymphoma kinase (ALK). http://clinicaltrials.gov/show/ NCT01634763 (Accessed 24 July 2013) 216 ClinicalTrials.gov. Phase I study of LDK378

in pediatric, malignancies with a genetic alteration in anaplastic lymphoma kinase (ALK). http://clinicaltrials.gov/show/ NCT01742286 (Accessed 24 July 2013) 217 ClinicalTrials.gov. Phase Ib study of

LDK378 and AUY922 in ALK-rearranged non-small cell lung cancer. http://clinicaltrials.gov/show/ NCT01772797 (Accessed 24 July 2013)

future science group

ALK-positive cancer: still a growing entity  218 ClinicalTrials.gov. A study of CH5424802/

RO5424802 in patients with ALKrearranged non-small cell lung cancer. http://clinicaltrials.gov/show/ NCT01871805 (Accessed 24 July 2013) 219 ClinicalTrials.gov. A study of RO5424802 in

patients with non-small cell lung cancer who have ALK mutation and failed crizotinib treatment. http://clinicaltrials.gov/show/NCT01801111 (Accessed 24 July 2013) 220 ClinicalTrials.gov. A clinical study testing

the safety and efficacy of CH5424802/ RO5424802 in patients with alk positive non-small cell lung cancer.

future science group

http://clinicaltrials.gov/show/ NCT01588028 (Accessed 24 July 2013)

Review

223 ClinicalTrials.gov. A Phase 1/2 study of the

221 ClinicalTrials.gov. Study of an

investigational drug, ASP3026, in patients with advanced malignancies (solid tumors and b-cell lymphoma). http://clinicaltrials.gov/show/ NCT01284192 (Accessed 24 July 2013) 222 ClinicalTrials.gov. Phase 1 safety study of

X-396, an oral alk inhibitor, in patients with advanced solid tumors. http://clinicaltrials.gov/show/ NCT01625234 (Accessed 24 July 2013)

oral ALK/EGFR inhibitor AP26113. http://clinicaltrials.gov/show/ NCT01449461 (Accessed 24 July 2013) 224 ClinicalTrials.gov. A study of ganetespib in

subjects with ALK-positive non-small-cell lung cancer (NSCLC) (CHIARA). http://clinicaltrials.gov/show/ NCT01562015 (Accessed 24 July 2013) 225 ClinicalTrials.gov. AUY922 for advanced

ALK-positive NSCLC. http://clinicaltrials.gov/show/ NCT01752400 (Accessed 24 July 2013)

www.futuremedicine.com

321