RESEARCH HIGHLIGHTS
A N T I C A N C E R AG E N T S
An alternative route to targeting telomere elongation
fergregory/iStock
Cancer cells rely on telomere elongation — either through activation of telomerase, or through the alternative lengthening of telomeres (ALT) pathway — to overcome replicative mortality. Although ALT is prevalent in several cancer types, it has not yet been exploited therapeutically. Now, writing in Science, Zou and colleagues demonstrate a crucial role for the protein kinase ATR in the regulation of the ALT pathway and show that smallmolecule ATR inhibitors selectively induce apoptosis in ALT-positive cancer cells.
Telomeres, which are critical for maintaining genomic integrity, are progressively shortened in actively dividing cells, eventually leading to cell death. However, malignant cells are able to lengthen telomeres, thereby promoting cellular immortality. Although most cancer cells typically achieve this through activation of telomerase, 5–10% of cancers instead use ALT, a less-understood mechanism that relies on recombination. Zou and colleagues therefore set out to further understand how ALT functions. During DNA replication, telomere repeat-containing RNA (TERRA) facilitates the transient association of replication protein A (RPA) with telomeric single-stranded DNA (ssDNA). The release of RPA from telomeres after S phase is thought to be an important mechanism to suppress homo logous recombination at telomeres. Interestingly, in cancer cell lines that were ALT-positive (established using a combination of several assays), they found that TERRA persistently associated with telomeres, leading to continued binding of RPA to telomeres after DNA replication. As recent studies have revealed a correlation of ALT with mutations in ATRX and loss of the chromatinremodelling protein ATRX in cancer, the authors next investigated whether ATRX loss may be contributing to the dysregulation of TERRA
NATURE REVIEWS | DRUG DISCOVERY
in ALT-positive cells. A series of in vitro studies incorporating small interfering RNA (siRNA)-mediated knockdown of ATRX revealed that loss of ATRX leads to increased levels of TERRA during G2/M and reduced release of RPA from telomeric ssDNA. As RPA–ssDNA recruits ATR, a key regulator of homologous recombination, Zou and colleagues explored whether ATR is functionally required for ALT. Indeed, ATR-specific siRNA and the small-molecule ATR inhibitor VE-821 disrupted ALT, selectively triggering telomere loss, chromosome fragmentation and apoptosis in ALT-positive cells. Finally, given the prevalence of ALT in osteosarcoma, the effect of ATR inhibition was tested on a panel of osteosarcoma cell lines. VE-821 and a second ATR inhibitor, AZ20, induced substantially higher levels of apoptosis in lines that were ALT-positive compared with those positive for telomerase. Similarly, VE-821 selectively killed ALT-positive glioma stem cells. Together, these findings suggest that ATR inhibition may be a novel, selective approach for the treatment of ALT-positive cancers. Sarah Crunkhorn ORIGINAL RESEARCH PAPER Flynn, R. L. et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347, 273–277 (2015)
VOLUME 14 | MARCH 2015 © 2015 Macmillan Publishers Limited. All rights reserved
A N T I C A N C E R AG E N T S
An alternative route to targeting telomere elongation
fergregory/iStock
Cancer cells rely on telomere elongation — either through activation of telomerase, or through the alternative lengthening of telomeres (ALT) pathway — to overcome replicative mortality. Although ALT is prevalent in several cancer types, it has not yet been exploited therapeutically. Now, writing in Science, Zou and colleagues demonstrate a crucial role for the protein kinase ATR in the regulation of the ALT pathway and show that smallmolecule ATR inhibitors selectively induce apoptosis in ALT-positive cancer cells.
Telomeres, which are critical for maintaining genomic integrity, are progressively shortened in actively dividing cells, eventually leading to cell death. However, malignant cells are able to lengthen telomeres, thereby promoting cellular immortality. Although most cancer cells typically achieve this through activation of telomerase, 5–10% of cancers instead use ALT, a less-understood mechanism that relies on recombination. Zou and colleagues therefore set out to further understand how ALT functions. During DNA replication, telomere repeat-containing RNA (TERRA) facilitates the transient association of replication protein A (RPA) with telomeric single-stranded DNA (ssDNA). The release of RPA from telomeres after S phase is thought to be an important mechanism to suppress homo logous recombination at telomeres. Interestingly, in cancer cell lines that were ALT-positive (established using a combination of several assays), they found that TERRA persistently associated with telomeres, leading to continued binding of RPA to telomeres after DNA replication. As recent studies have revealed a correlation of ALT with mutations in ATRX and loss of the chromatinremodelling protein ATRX in cancer, the authors next investigated whether ATRX loss may be contributing to the dysregulation of TERRA
NATURE REVIEWS | DRUG DISCOVERY
in ALT-positive cells. A series of in vitro studies incorporating small interfering RNA (siRNA)-mediated knockdown of ATRX revealed that loss of ATRX leads to increased levels of TERRA during G2/M and reduced release of RPA from telomeric ssDNA. As RPA–ssDNA recruits ATR, a key regulator of homologous recombination, Zou and colleagues explored whether ATR is functionally required for ALT. Indeed, ATR-specific siRNA and the small-molecule ATR inhibitor VE-821 disrupted ALT, selectively triggering telomere loss, chromosome fragmentation and apoptosis in ALT-positive cells. Finally, given the prevalence of ALT in osteosarcoma, the effect of ATR inhibition was tested on a panel of osteosarcoma cell lines. VE-821 and a second ATR inhibitor, AZ20, induced substantially higher levels of apoptosis in lines that were ALT-positive compared with those positive for telomerase. Similarly, VE-821 selectively killed ALT-positive glioma stem cells. Together, these findings suggest that ATR inhibition may be a novel, selective approach for the treatment of ALT-positive cancers. Sarah Crunkhorn ORIGINAL RESEARCH PAPER Flynn, R. L. et al. Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors. Science 347, 273–277 (2015)
VOLUME 14 | MARCH 2015 © 2015 Macmillan Publishers Limited. All rights reserved
