PARP inhibitors (PARPis) were initially developed as DNA repair inhibitors that inhibit the catalytic activity of PARP1 and PARP2 and are expected to induce synthetic lethality in BRCA ‐ or homologous recombination (HR)‐deficient tumors. However, the clinical indications for PARPis are not necessarily limited to BRCA mutations or HR deficiency; BRCA wild‐type and HR‐proficient cancers can also derive some benefit from PARPis. These facts are interpretable by an additional primary antitumor mechanism of PARPis named PARP trapping, resulting from the stabilization of PARP‐DNA complexes. Favorable response to platinum derivatives (cisplatin and carboplatin) in preceding treatment is used as a clinical biomarker for some PARPis, implying that sensitivity factors for platinum derivatives and PARPis are mainly common. Such common sensitivity factors include not only HR defects (HRD) but also additional factors. One of them is Schlafen 11 ( SLFN11 ), a putative DNA/RNA helicase, that sensitizes cancer cells to a broad type of DNA‐damaging agents, including platinum and topoisomerase inhibitors. Mechanistically, SLFN11 induces a lethal replication block in response to replication stress (ie, DNA damage). As SLFN11 acts upon replication stress, trapping PARPis can activate SLFN11. Preclinical models show the importance of SLFN11 in PARPi sensitivity. However, the relevance of SLFN11 in PARPi response is less evident in clinical data compared with the significance of SLFN11 for platinum sensitivity. In this review, we consider the reasons for variable indications of PARPis resulting from clinical outcomes and review the mechanisms of action for PARPis as anticancer agents.
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) induce synthetic lethality in breast cancer gene (BRCA)-deficient tumors. Besides the original model proposed by accumulation of double-strand DNA breaks due to the impaired homologous recombination, accumulation of single-strand DNA (ssDNA) gaps due to impaired BRCA-mediated Okazaki fragment processing has emerged as an alternative mechanism of synthetic lethality. Accordingly, PARPis induce ssDNA gaps behind a replication fork in BRCA-deficient cells. Schlafen 11 (SLFN11), a member of the SLFN family, binds replication protein A (RPA)-coated ssDNA gaps and sensitizes cancer cells to DNA-damaging anticancer agents. These facts motivated us to examine the combinational effects of SLFN11 and BRCA-deficiency on PARPis sensitivity. Here, we show that SLFN11 and BRCA2-deficiency synergistically increased sensitivity to PARPis (talazoparib, niraparib, olaparib, and veliparib) at specific concentrations, where SLFN11 alone showed marginal effects. Using chromatin-bound proteins and alkaline BrdU comet assays in human cancer cells, we revealed that ssDNA gaps induced by PARPis were increased by SLFN11 or BRCA2-deficiency and that the combination of the two had the greatest effect. SLFN11 was recruited to and colocalized with chromatin-bound RPA2 under PARPis. SLFN11 recruited around a fork under DNA damage blocked replication, whereas SLFN11 recruited behind a fork under PARPis did not. Chromatin recruitment of SLFN11 and RPA2 was attenuated by the MRE11 inhibitor mirin. Hence, our studies showed that BRCA2-deficiency increased ssDNA gaps behind a fork under PARPis treatment, where SLFN11 bound and further increased the gaps. Our findings provide a mechanistic understanding of favorable responses to PARPis in SLFN11-proficient and BRCA-deficient tumors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.