Mechanisms of PARP1 inhibitor resistance and their implications for cancer treatment

Abstract

The discovery of synthetic lethality as a result of the combined loss of PARP1 and BRCA has revolutionized the treatment of DNA repair-deficient cancers. With the development of PARP inhibitors, patients displaying germline or somatic mutations in BRCA1 or BRCA2 were presented with a novel therapeutic strategy. However, a large subset of patients do not respond to PARP inhibitors. Furthermore, many of those who do respond eventually acquire resistance. As such, combating de novo and acquired resistance to PARP inhibitors remains an obstacle in achieving durable responses in patients. In this review, we touch on some of the key mechanisms of PARP inhibitor resistance, including restoration of homologous recombination, replication fork stabilization and suppression of single-stranded DNA gap accumulation, as well as address novel approaches for overcoming PARP inhibitor resistance.

CRISPR knockout genome-wide screens identify the HELQ-RAD52 axis in regulating the repair of cisplatin-induced single stranded DNA gaps

“…In line with these previous reports, PRIMPOL-overexpressing cells showed increased ssDNA gap formation in response to multiple replication stress-inducing agents, including cisplatin and hydroxyurea (HU), as well as the PARP1 inhibitor olaparib (Figure 1B-E, Supplementary Figure S1A-H). Accumulation of ssDNA gaps was detected, in both HeLa and U2OS cells, using two different assays previously employed by us and others to measure nascent strand gaps backgrounds (Berti et al, 2013; Cantor, 2021; Cong et al, 2021b; Dhoonmoon et al, 2022; Jackson et al, 2021; Jackson and Moldovan, 2022; Kang et al, 2021; Panzarino et al, 2021; Quinet et al, 2020; Ray Chaudhuri et al, 2012; Simoneau et al, 2021; Thakar et al, 2022; Thakar et al, 2020; Thakar and Moldovan, 2021; Tirman et al, 2021), namely the BrdU alkaline comet assay (Figure 1B,C; Supplementary Figure S1A-D) and the S1 nuclease DNA fiber assay (Figure 1D,E; Supplementary Figure S1E-H).…”

“…Previously, accumulation of ssDNA gaps in certain genetic backgrounds, particularly those with BRCA mutations, were shown to correlate with chemosensitivity (Berti et al, 2013; Cantor, 2021; Cong et al, 2021b; Dhoonmoon et al, 2022; Jackson et al, 2021; Jackson and Moldovan, 2022; Kang et al, 2021; Panzarino et al, 2021; Quinet et al, 2020; Ray Chaudhuri et al, 2012; Simoneau et al, 2021; Thakar et al, 2022; Thakar et al, 2020; Thakar and Moldovan, 2021; Tirman et al, 2021). On the other hand, recent findings suggest that chemosensitivity caused by BRCA2 inactivation mainly reflects the role of BRCA2 in HR, rather than its roles in ssDNA gap suppression and fork protection (Feng and Jasin, 2017; Lim et al, 2024).…”

“…BRCA-mutant tumors are highly sensitive to genotoxic chemotherapy (Mylavarapu et al, 2018). More recently, targeted therapies for BRCA-mutant tumors have been developed, relying on drugs inhibiting PARP1, which render cells hyper-reliant on the BRCA pathway (Bryant et al, 2005; Farmer et al, 2005; Jackson and Moldovan, 2022). Treatment of BRCA-mutant cells with PARP inhibitors also results in generation of ssDNA gaps, reversed forks prone to degradation, and DSBs (Bryant et al, 2005; Cong et al, 2021a; Farmer et al, 2005; Ray Chaudhuri et al, 2016).…”

“…More recently, its fork protection role was proposed (Bhat and Cortez, 2018; Guillemette et al, 2015; Quinet et al, 2017; Ray Chaudhuri et al, 2016; Taglialatela et al, 2017; Thakar and Moldovan, 2021). Finally, recent work highlighted gap suppression as better correlating with chemotherapy response in particular genetic backgrounds (Berti et al, 2013; Cantor, 2021; Cong et al, 2021b; Dhoonmoon et al, 2022; Jackson et al, 2021; Jackson and Moldovan, 2022; Kang et al, 2021; Panzarino et al, 2021; Quinet et al, 2020; Ray Chaudhuri et al, 2012; Simoneau et al, 2021; Thakar et al, 2022; Thakar et al, 2020; Thakar and Moldovan, 2021; Tirman et al, 2021). However, experiments using separation of function BRCA2 mutants which are proficient for HR but defective in fork protection and gap suppression, suggest that BRCA2 promotes therapy resistance primarily through HR (Feng and Jasin, 2017; Lim et al, 2024).…”

BRCA Mutations: The Achilles Heel of Breast, Ovarian and Other Epithelial Cancers

“…In this respect, synthetic lethal interactions between PARPi and BRCA mutation patients is a convincing example of how the fundamental discovery in molecular medicine can be translated into clinical cancer therapy. However, the next step problem is the multifariousness of PARPi resistance mechanisms (recently reviewed in depth by Jackson and Moldavan [139]) that eventually arise in BRCA mutant patients in response to the therapy. In particular, Alu mobile elements regulate the expression of many genes, including the ones that mediate DNA repair [140].…”