TY - JOUR
T1 - Targeting the replication stress response through synthetic lethal strategies in cancer medicine
AU - Ngoi, Natalie Y.L.
AU - Pham, Melissa M.
AU - Tan, David S.P.
AU - Yap, Timothy A.
N1 - Funding Information:
N.Y.L.N. is supported by the National Medical Research Council, Singapore (MOH-FLWSHP19may-0006). D.S.P.T. is supported by the National Medical Research Council, Singapore (CSAINV16may008), and has received charitable research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund. T.A.Y. is supported by MD Anderson Cancer Center Support grant (NIH/NCI P30 CA016672), the US Department of Defense Ovarian Cancer Research Program (OC200482), and the V Foundation Clinical Scholar Program (VC2020-001). N.Y.L.N. received honoraria from AstraZeneca and Janssen. D.S.P.T. received research funding from AstraZeneca, Bayer, and Karyopharm and honoraria from AstraZeneca, MSD, Tessa Therapeutics, Novartis, Bayer, and Genmab. T.A.Y. received research funding (paid to his institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals. In addition, he has received fees for consulting with Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian, and Zai Labs. M.P. has no interests declared. T.A.Y. conceptualized the project. N.Y.L.N. M.P. and T.A.Y. curated the data. N.Y.L.N. and M.P. prepared the original draft. N.Y.L.N. M.P. D.S.P.T. and T.A.Y. reviewed and edited the paper. N.Y.L.N. and T.A.Y. visualized the project. D.S.P.T. and T.A.Y. supervised the work. N.Y.L.N. was the project administrator.
Funding Information:
N.Y.L.N. received honoraria from AstraZeneca and Janssen. D.S.P.T. received research funding from AstraZeneca, Bayer, and Karyopharm and honoraria from AstraZeneca, MSD, Tessa Therapeutics, Novartis, Bayer, and Genmab. T.A.Y. received research funding (paid to his institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals. In addition, he has received fees for consulting with Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian, and Zai Labs. M.P. has no interests declared.
Funding Information:
N.Y.L.N. is supported by the National Medical Research Council , Singapore ( MOH-FLWSHP19may-0006 ). D.S.P.T. is supported by the National Medical Research Council , Singapore ( CSAINV16may008 ), and has received charitable research funding from the Pangestu Family Foundation Gynaecological Cancer Research Fund . T.A.Y. is supported by MD Anderson Cancer Center Support grant (NIH/NCI P30 CA016672 ), the US Department of Defense Ovarian Cancer Research Program ( OC200482 ), and the V Foundation Clinical Scholar Program ( VC2020-001 ).
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/10
Y1 - 2021/10
N2 - The replication stress response (RSR) involves a downstream kinase cascade comprising ataxia telangiectasia-mutated (ATM), ATM and rad3-related (ATR), checkpoint kinases 1 and 2 (CHK1/2), and WEE1-like protein kinase (WEE1), which cooperate to arrest the cell cycle, protect stalled forks, and allow time for replication fork repair. In the presence of elevated replicative stress, cancers are increasingly dependent on RSR to maintain genomic integrity. An increasing number of drug candidates targeting key RSR nodes, as monotherapy through synthetic lethality, or through rational combinations with immune checkpoint inhibitors and targeted therapies, are demonstrating promising efficacy in early phase trials. RSR targeting is also showing potential in reversing PARP inhibitor resistance, an important area of unmet clinical need. In this review, we introduce the concept of targeting the RSR, detail the current landscape of monotherapy and combination strategies, and discuss emerging therapeutic approaches, such as targeting Polθ.
AB - The replication stress response (RSR) involves a downstream kinase cascade comprising ataxia telangiectasia-mutated (ATM), ATM and rad3-related (ATR), checkpoint kinases 1 and 2 (CHK1/2), and WEE1-like protein kinase (WEE1), which cooperate to arrest the cell cycle, protect stalled forks, and allow time for replication fork repair. In the presence of elevated replicative stress, cancers are increasingly dependent on RSR to maintain genomic integrity. An increasing number of drug candidates targeting key RSR nodes, as monotherapy through synthetic lethality, or through rational combinations with immune checkpoint inhibitors and targeted therapies, are demonstrating promising efficacy in early phase trials. RSR targeting is also showing potential in reversing PARP inhibitor resistance, an important area of unmet clinical need. In this review, we introduce the concept of targeting the RSR, detail the current landscape of monotherapy and combination strategies, and discuss emerging therapeutic approaches, such as targeting Polθ.
KW - PARP inhibition resistance
KW - combination therapy
KW - replicative stress response
KW - synthetic lethality
UR - http://www.scopus.com/inward/record.url?scp=85108954003&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85108954003&partnerID=8YFLogxK
U2 - 10.1016/j.trecan.2021.06.002
DO - 10.1016/j.trecan.2021.06.002
M3 - Review article
C2 - 34215565
AN - SCOPUS:85108954003
SN - 2405-8033
VL - 7
SP - 930
EP - 957
JO - Trends in Cancer
JF - Trends in Cancer
IS - 10
ER -