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PAK1 in non-metastatic ccRCC

3 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J. Clin. 2014; 64: 9–29. 4 Ljungberg B, Hanbury DC, Kuczyk MA et al. Renal cell carcinoma guideline. Eur. Urol. 2007; 51: 1502–10. 5 Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J. Urol. 2000; 163: 1090–5; quiz 295. 6 Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J. Urol. 2001; 166: 63–7. 7 Zisman A, Pantuck AJ, Dorey F et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J. Clin. Oncol. 2001; 19: 1649–57. 8 Frank I, Blute ML, Cheville JC, Lohse CM, Weaver AL, Zincke H. An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J. Urol. 2002; 168: 2395–400. 9 Eichelberg C, Junker K, Ljungberg B, Moch H. Diagnostic and prognostic molecular markers for renal cell carcinoma: a critical appraisal of the current state of research and clinical applicability. Eur. Urol. 2009; 55: 851–63. 10 Parker AS, Leibovich BC, Lohse CM et al. Development and evaluation of BioScore: a biomarker panel to enhance prognostic algorithms for clear cell renal cell carcinoma. Cancer 2009; 115: 2092–103. 11 Kumar R, Gururaj AE, Barnes CJ. p21-activated kinases in cancer. Nat. Rev. Cancer 2006; 6: 459–71. 12 O’Sullivan GC, Tangney M, Casey G, Ambrose M, Houston A, Barry OP. Modulation of p21-activated kinase 1 alters the behavior of renal cell carcinoma. Int. J. Cancer 2007; 121: 1930–40. 13 Liu H, Xu J, Zhou L et al. Hepatitis B virus large surface antigen promotes liver carcinogenesis by activating the Src/PI3K/Akt pathway. Cancer Res. 2011; 71: 7547–57. 14 Jocham D, Richter A, Hoffmann L et al. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 2004; 363: 594–9. 15 Aitchison M, Bray CA, Van Poppel H et al. Adjuvant 5-flurouracil, alphainterferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/National Cancer Research Institute trial. Eur. J. Cancer 2014; 50: 70–7. 16 Pizzocaro G, Piva L, Colavita M et al. Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. J. Clin. Oncol. 2001; 19: 425–31. 17 Shrestha Y, Schafer EJ, Boehm JS et al. PAK1 is a breast cancer oncogene that coordinately activates MAPK and MET signaling. Oncogene 2012; 31: 3397–408.

18 Rettig M, Trinidad K, Pezeshkpour G et al. PAK1 kinase promotes cell motility and invasiveness through CRK-II serine phosphorylation in non-small cell lung cancer cells. PLoS One 2012; 7: e42012. 19 Qing H, Gong W, Che Y et al. PAK1-dependent MAPK pathway activation is required for colorectal cancer cell proliferation. Tumour Biol. 2012; 33: 985–94. 20 Siu MK, Wong ES, Chan HY et al. Differential expression and phosphorylation of Pak1 and Pak2 in ovarian cancer: effects on prognosis and cell invasion. Int. J. Cancer 2010; 127: 21–31. 21 Redelman-Sidi G, Iyer G, Solit DB, Glickman MS. Oncogenic activation of Pak1-dependent pathway of macropinocytosis determines BCG entry into bladder cancer cells. Cancer Res. 2013; 73: 1156–67. 22 Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat. Rev. Cancer 2009; 9: 631–43. 23 Kissil JL, Wilker EW, Johnson KC, Eckman MS, Yaffe MB, Jacks T. Merlin, the product of the Nf2 tumor suppressor gene, is an inhibitor of the p21activated kinase, Pak1. Mol. Cell 2003; 12: 841–9. 24 Xu J, Liu H, Chen L et al. Hepatitis B virus X protein confers resistance of hepatoma cells to anoikis by up-regulating and activating p21-activated kinase 1. Gastroenterology 2012; 143: 199–212 e4. 25 Hew MN, Zondervan PJ, Guven S, de la Rosette J, Laguna MP. Prognostic models and factors for patients with renal-cell carcinoma: a survey on their use among urologists. J. Endourol. 2013; 27: 790–9. 26 Holm C, Rayala S, Jirstrom K, Stal O, Kumar R, Landberg G. Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients. J. Natl. Cancer Inst. 2006; 98: 671–80. 27 Park J, Kim JM, Park JK et al. Association of p21-activated kinase (PAK)-1 activity with aggressive tumor behavior and poor prognosis of head and neck cancer. Head Neck 2014. doi: 10.1002/hed.23695. 28 Goc A, Al-Azayzih A, Abdalla M et al. P21 activated kinase-1 (Pak1) promotes prostate tumor growth and microinvasion via inhibition of transforming growth factor beta expression and enhanced matrix metalloproteinase 9 secretion. J. Biol. Chem. 2013; 288: 3025–35. 29 Ong CC, Jubb AM, Haverty PM et al. Targeting p21-activated kinase 1 (PAK1) to induce apoptosis of tumor cells. Proc. Natl. Acad. Sci. U. S. A. 2011; 108: 7177–82. 30 Zhu G, Wang Y, Huang B et al. A Rac1/PAK1 cascade controls beta-catenin activation in colon cancer cells. Oncogene 2012; 31: 1001–12.

Supporting information Additional Supporting Information may be found in the online version of this article at the publisher’s web-site: Table S1. Univariate Cox regression analysis of overall survival and recurrence-free survival of non-metastatic ccRCC patients.

Original Article: Editorial Comment Clinical Investigation Editorial Comment to p21-activated kinase 1 predicts recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma Although almost all non-metastatic renal cell cancers (RCC) can be cured by partial or radical nephrectomies, 20–30% of patients eventually relapse and develop metastases during follow up.1 The prognosis of patients after nephrectomies for these non-metastatic RCC depends on the TNM stage, grade and histology. Based on these traditional scores, several postoperative prognostic models, such as the Kattan nomogram from the Memorial Sloan-Kettering Cancer Center, the University of California Los Angeles Integrated Staging System, and the Mayo Clinic stage, size, grade and necrosis score have been designed to identify patients at high risk of disease development after nephrectomy.2–4 © 2015 The Japanese Urological Association

In this issue of the International Journal of Urology, Zhu et al. reported the results of a single institutional retrospective study of East Asian patients with localized clear cell RCC that was designed to determine the outcomes of patients with this disease and the prognostic factors.5 Zhu et al. examined p21activated kinase 1 (PAK1), which is a serine/threonine kinase that orchestrates cytoskeletal remodeling and cell motility. PAK1 has been shown to play various oncogenic roles in promoting cell proliferation, regulating apoptosis and accelerating mitotic abnormalities, all of which result in tumor formation and invasiveness.5 They showed that high PAK1 expression indicated poor survival and early disease recurrence in patients 453

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with non-metastatic clear cell RCC, particularly those with early T1–2 stage disease. Furthermore, PAK1 expression was identified as an independent adverse prognostic factor for survival and recurrence. The predictive accuracy of the traditional University of California Los Angeles Integrated Staging System, and Mayo Clinic stage, size, grade and necrosis prognostic models was improved when PAK1 expression was added. The prognostic factor of patients after local surgery for nonmetastatic RCC is an important issue for future research. As described in the study by Zhu et al., none of the trials carried out during the cytokine era showed clinical benefit in the adjuvant setting.5 However, based on the efficacies in the metastatic setting, various trials using tyrosine kinase inhibitors have been proposed as adjuvant therapy for high-risk non-metastatic RCC after surgery with radical intent. The ASSURE (Adjuvant Sorafenib or Sunitinib for Unfavorable Renal carcinoma) trial compares adjuvant sorafenib and sunitinib, and the S-TRAC (Sunitinib Treatment of Renal Adjuvant Cancer) trial will assess the effectiveness of 1 year of adjuvant treatment with sunitinib versus placebo in these patients. The SORCE (Sorafenib with Placebo in Patients with Resected Primary Renal Cell Carcinoma) trial is a three-arm study that will compare 3 years of treatment with sorafenib against 1 year of treatment with sorafenib plus 2 years of placebo against placebo for 3 years. Furthermore, the PROTECT (Study to Evaluate Pazopanib as an Adjuvant Treatment for Localized Renal Cell Carcinoma) trial of adjuvant pazopanib versus placebo is also being evaluated as adjuvant therapy after nephrectomy. We eagerly await the results of these studies, as they will help define the potential role of tyrosine kinase inhibitors in the adjuvant setting for patients with high risk of disease recurrence. The study of Zhu et al. could play an important role in the era of adjuvant tyrosine kinase inhibitors for RCC. Although a multicenter,

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prospective study is necessary to verify that PAK1 is an indicator of poor prognosis after local surgery, stratification using PAK1 expression in these adjuvant setting clinical studies should be interesting. Takeshi Yuasa M.D., Ph.D. Department of Urology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Ariake, Tokyo, Japan [email protected] DOI: 10.1111/iju.12732

Conflict of interest T Yuasa received remuneration for a lecture from Pfizer Japan (Tokyo, Japan) and Novartis Pharma Japan (Tokyo, Japan).

References 1 Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics. CA Cancer J. Clin. 2014; 64: 9–29. 2 Tsui KH, Shvarts O, Smith RB, Figlin RA, deKernion JB, Belldegrun A. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J. Urol. 2000; 163: 1090–5; quiz 295. 3 Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P. A postoperative prognostic nomogram for renal cell carcinoma. J. Urol. 2001; 166: 63–7. 4 Zisman A, Pantuck AJ, Dorey F et al. Improved prognostication of renal cell carcinoma using an integrated staging system. J. Clin. Oncol. 2001; 19: 1649. 5 Zhu Y, Xu L, An H, Liu W, Wang Z, Xu J. p21-activated kinase 1 predicts recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma. Int. J. Urol. 2015; 22: 447–53.

© 2015 The Japanese Urological Association

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Editorial Comment to p21-activated kinase 1 predicts recurrence and survival in patients with non-metastatic clear cell renal cell carcinoma.

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