Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response

Abstract

Editorial summaryInhibitors of poly(ADP-ribose) polymerase (PARPi) have entered the clinic for the treatment of patients with cancers that lack homology-directed DNA repair, but drug resistance remains a clinical hurdle. Recent advances in the identification of PARPi resistance mechanisms have yielded a better understanding of DNA end protection and the relevance of endogenous poly(ADP-ribose) glycohydrolase, highlighting new vulnerabilities.

Poly (ADP-Ribose) Polymerase Inhibitors: Talazoparib in Ovarian Cancer and Beyond

“…Loss of 53BP1 function by either mutation or downregulation accelerates the BRCA1-independent endresection and provides PARP inhibitor resistance [111]. It has been demonstrated that the inactivation of downstream factors of 53BP1-mediated repair, typically RIF1 and REV7, also leads to the restoration of DNA end resection, and consequently promotes homology-mediated repair [112]. Loss of the 53BP1-RIF1-REV7 pathway in PARP inhibitorresistant BRCA1-deficient cells results in hypersensitivity to ionizing radiation.…”

Regulation of cGAS‐Mediated Immune Responses and Immunotherapy

“…These outcomes reveal additional cGAS functions, which could be used to understand its contribution to diseases related to genome instability 189. In another study, cGAS has recently been shown to associate genomic instability with the innate immune response 190. Lately, it is uncovered in mouse and human models that cGAS hinders HR.…”

“…The ensuing DNA damage incites molecular relocation of cGAS in a manner reliant on importin‐α, and the consequent phosphorylation of cGAS at the site of tyrosine 215 induced by B‐lymphoid tyrosine kinase, which encourages the intracellular cytosolic maintenance of cGAS. Similarly, in the nucleus, the recruitment of cGAS to DSBs occurs and communicates with poly [ADP‐ribose] polymerase 1 (PARP‐1) through the interaction with poly (ADP‐ribose) 190. The cGAS‐PARP1 cooperation blocks development of the PARP1–Timeless assembly, and in this way, represses HR.…”

“…[189] In another study, cGAS has recently been shown to associate genomic instability with the innate immune response. [190] Lately, it is uncovered in mouse and human models that cGAS hinders HR. The ensuing DNA damage incites molecular relocation of cGAS in a manner reliant on importin-α, and the consequent phosphorylation of cGAS at the site of tyrosine 215 induced by B-lymphoid tyrosine kinase, which encourages the intracellular cytosolic maintenance of cGAS.…”

“…Similarly, in the nucleus, the recruitment of cGAS to DSBs occurs and communicates with poly [ADPribose] polymerase 1 (PARP-1) through the interaction with poly (ADP-ribose). [190] The cGAS-PARP1 cooperation blocks development of the PARP1-Timeless assembly, and in this way, represses HR. They further demonstrated that knockdown of cGAS impedes DNA damage and restrains tumor development both in vitro and in vivo.…”