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Review
. 2020 Jun 18;78(6):1070-1085.
doi: 10.1016/j.molcel.2020.04.035. Epub 2020 May 26.

Biomarker-Guided Development of DNA Repair Inhibitors

Affiliations
Review

Biomarker-Guided Development of DNA Repair Inhibitors

James M Cleary et al. Mol Cell. .

Abstract

Anti-cancer drugs targeting the DNA damage response (DDR) exploit genetic or functional defects in this pathway through synthetic lethal mechanisms. For example, defects in homologous recombination (HR) repair arise in cancer cells through inherited or acquired mutations in BRCA1, BRCA2, or other genes in the Fanconi anemia/BRCA pathway, and these tumors have been shown to be particularly sensitive to inhibitors of the base excision repair (BER) protein poly (ADP-ribose) polymerase (PARP). Recent work has identified additional genomic and functional assays of DNA repair that provide new predictive and pharmacodynamic biomarkers for these targeted therapies. Here, we examine the development of selective agents targeting DNA repair, including PARP inhibitors; inhibitors of the DNA damage kinases ataxia-telangiectasia and Rad3 related (ATR), CHK1, WEE1, and ataxia-telangiectasia mutated (ATM); and inhibitors of classical non-homologous end joining (cNHEJ) and alternative end joining (Alt EJ). We also review the biomarkers that guide the use of these agents and current clinical trials with these therapies.

Keywords: DNA repair; PARP inhibitor; cell-cycle kinases; polymerase theta.

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Conflict of interest statement

Declaration of Interests J.M.C. received research funding from Merck, AstraZeneca, and Tesaro; has served as a consultant to Bristol Myers Squib; and received travel funding from Bristol Myers Squib and Roche. A.J.A. has consulted for Oncorus, Arrakis Therapeutics, and Merck & Co. and has research funding from Mirati Therapeutics and Deerfield that are unrelated to this project. G.I.S. has received research funding from Eli Lilly, Merck KGaA/EMD-Serono, Merck, and Sierra Oncology; has served on advisory boards for Pfizer, Eli Lilly, G1 Therapeutics, Roche, Merck KGaA/EMD-Serono, Sierra Oncology, Bicycle Therapeutics, Fusion Pharmaceuticals, Cybrexa Therapeutics, Astex, Almac, Ipsen, Bayer, Angiex, Daiichi Sankyo, Seattle Genetics, Boehringer Ingelheim, ImmunoMet, Asana, Artios, Atrin, and Concarlo Holdings; and holds a patent entitled, “Dosage regimen for sapacitabine and seliciclib,” also issued to Cyclacel Pharmaceuticals, and a pending patent entitled, “Compositions and Methods for Predicting Response and Resistance to CDK4/6 Inhibition,” together with Liam Cornell. A.D.D. is a consultant/advisory board member for Lilly Oncology, Merck-EMD Serono, Intellia Therapeutics, Sierra Oncology, Cyteir Therapeutics, Third Rock Ventures, AstraZeneca, Ideaya, and Cedilla Therapeutics; a stockholder in Ideaya, Cedilla Therapeutics, and Cyteir; and reports receiving commercial research grants from Lilly Oncology and Merck-EMD Serono.

Figures

Figure 1:
Figure 1:. Mechanisms of PARP Inhibitor and POLϴ Inhibitor Cytotoxicity.
A. PARP inhibition blocks BER single-strand DNA repair. The inability to repair single-strand DNA breaks leads to the accumulation of double-strand DNA breaks. In HR-deficient cancers, cells are dependent on error-prone cNHEJ to repair double strand DNA breaks. The large number of genomic errors introduced by cNHEJ leads to catastrophic DNA damage. B. PARP inhibitor trapping blocks DNA replication and DNA repair. C. Polϴ inhibition blocks the Alt-EJ pathway from repairing double-stand DNA breaks. PARP and POLθ are known to cooperate in Alt-EJ. Inhibition of POLθ, and to a lesser extent, inhibition of PARP, results in the loss of Alt-EJ and the accumulation of toxic RAD51 foci. This mechanism provides a rationale for combining a PARP inhibitor with a POLθ inhibitor for cancer treatment. The combination may be synergistic since it leads to toxic RAD51 accumulation and cell death.
Figure 2:
Figure 2:. The ATR/CHK1/WEE1 pathway compensates for the replicative stress induced by gemcitabine.
Gemcitabine causes replicative stress by irreversibly inhibiting ribonucleotide reductase and thereby decreasing dNTP concentration. Decreased dNTP concentration causes stalled replication forks. In response to this replicative stress, the ATR/CHK1/WEE1 pathway is activated and this leads to stabilization of the replicative forks. However, inhibitors of the ATR/CHK1/WEE1 pathway block this compensatory pathway. This leads to persistence of unstable replication forks and ultimately causes genomic catastrophe leading to cancer cell death.
Figure 3:
Figure 3:. Hyperactivation of the ATR/CHK1/WEE1 pathway leads to acquired resistance to PARP inhibitors.
PARP inhibitors, through inhibition of single-strand DNA repair and PARP inhibitor trapping, causes stalled replication forks and ultimately cell death in HR-deficient cancers. Cancer cells can develop resistance to PARP inhibitors by hyperactivation of the compensatory ATR/CHK1/WEE1 pathway, leading to stabilization of replication forks.

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