Targeting the DNA Damage Response Beyond poly(ADP-Ribose) Polymerase Inhibitors: Novel Agents and Rational Combinations

Authors

Natalie Y L Ngoi
Shannon N Westin
Timothy A Yap

Publication Date

9-1-2022

Journal

Current Opinion in Oncology

Abstract

Purpose of review: Poly(ADP-ribose) polymerase (PARP) inhibitors have transformed treatment paradigms in multiple cancer types defined by homologous recombination deficiency (HRD) and have become the archetypal example of synthetic lethal targeting within the DNA damage response (DDR). Despite this success, primary and acquired resistance to PARP inhibition inevitability threaten the efficacy and durability of response to these drugs. Beyond PARP inhibitors, recent advances in large-scale functional genomic screens have led to the identification of a steadily growing list of genetic dependencies across the DDR landscape. This has led to a wide array of novel synthetic lethal targets and corresponding inhibitors, which hold promise to widen the application of DDR inhibitors beyond HRD and potentially address PARP inhibitor resistance.

Recent findings: In this review, we describe key synthetic lethal interactions that have been identified across the DDR landscape, summarize the early phase clinical development of the most promising DDR inhibitors, and highlight relevant combinations of DDR inhibitors with chemotherapy and other novel cancer therapies, which are anticipated to make an impact in rationally selected patient populations.

Summary: The DDR landscape holds multiple opportunities for synthetic lethal targeting with multiple novel DDR inhibitors being evaluated on early phase clinical trials. Key challenges remain in optimizing the therapeutic window of ATR and WEE1 inhibitors as monotherapy and in combination approaches.

Keywords

Antineoplastic Agents, DNA Damage, DNA Repair, Humans, Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors

DOI

10.1097/CCO.0000000000000867

PMID

35787597

PMCID

PMC9371461

PubMedCentral® Posted Date

9-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes