Strategies in Overcoming Homologous Recombination Proficiency and PARP Inhibitor Resistance

Abstract

Ovarian cancer is the second most common gynecologic malignancy in the United States (US) and the most common cause of gynecologic cancer-related death. The majority of ovarian cancers ultimately recur despite excellent response rates to upfront platinum and taxane-based chemotherapy. Maintenance therapy after frontline treatment has emerged in recent years as an effective tool for extending the platinum-free interval of these patients. Maintenance therapy with poly (ADP-ribose) polymerase inhibitors (PARPi) in particular has become part of standard of care in the upfront setting and in patients with platinum-sensitive disease. HR deficient (HRD) tumors have a nonfunctioning homologous recombination repair (HRR) pathway and respond well to PARPi, which takes advantage of synthetic lethality by concomitantly impairing DNA repair mechanisms. Conversely, patients with a functioning HRR pathway, i.e. HR proficient (HRP) tumors, can still elicit benefit from PARPi, but the efficacy is not as remarkable as what is seen in HRD tumors. PARPi are ineffective in some patients due to HR proficiency, which is either inherent to the tumor or potentially acquired as a method of therapeutic resistance. This review seeks to outline current strategies employed by clinicians and scientists to overcome PARPi resistanceeither acquired or inherent to the tumor.

Deubiquitination of FBP1 by USP7 blocks FBP1–DNMT1 interaction and decreases the sensitivity of pancreatic cancer cells to PARP inhibitors

“…The BRCA2 mutation status seems to be dispensable for the effect of FBP1 on the sensitivity of pancreatic cancer to Olaparib. However, the BRCA2 alterations are not the only alterations responsible for homologous recombination (HR) defects and Olaparib sensitivity [ 20 ]. The specific mechanism by which FBP1 regulates the sensitivity of pancreatic cancer to Olaparib and whether FBP1 can modulate the sensitivity to Olaparib without affecting the HR pathway needs further study.…”

PARP Inhibitors Display Differential Efficacy in Models of BRCA Mutant High-Grade Serous Ovarian Cancer

“…While amongst the most efficacious molecular target drugs of recent times, tumours can display innate or acquired resistance to PARPis. The reasons for this include innate HRR proficiency, reversion of BRCA mutations or mutations in other HRR-related genes such as PALB2 or RAD51C, loss of BRCA1 methylation that re-establishes HRR proficiency, the increase in expression of drug efflux pumps such as the MDR1 (p-glycoprotein) gene, aberrant replication fork protection and down-regulation of PARP proteins themselves, possibly as a result of PARP trapping [32,33].…”

Overcoming PARP Inhibitor and Platinum Resistance with WEE1 Inhibitors in Ovarian Cancer

“…healthbook Times Oncology Hematology healthbook.ch October, 2021 M EC H A N I S M S O F PA R P i R E S I S TA N C E Homologous recombination (HR) has been identified as one of the main pathways involved in repairing double-strand (DSB) DNA breaks resulting from DNA damage. 19 In tumor cells with defective HR (homologous recombination deficiency, HRD) repair pathways, PARP modulates repair of DNA single-strand (SBB) breaks and thus enables cell survival. [17][18][19] In tumor cells with HRD, PARPi trap PARP on DNA to block SSB repair, promoting the accumulation of fatal DSB and DNA damage and triggering cell death through the welldescribed mechanism of synthetic lethality.…”

“…19 In tumor cells with defective HR (homologous recombination deficiency, HRD) repair pathways, PARP modulates repair of DNA single-strand (SBB) breaks and thus enables cell survival. [17][18][19] In tumor cells with HRD, PARPi trap PARP on DNA to block SSB repair, promoting the accumulation of fatal DSB and DNA damage and triggering cell death through the welldescribed mechanism of synthetic lethality. [19][20][21] Approximately 50% of all EOCs are characterized by HRD, mainly due to genomic alterations in HR genes, including but not limited to BRCA1/2, and this correlates with a higher sensitivity to platinum-based chemotherapy and PARPi.…”

“…[17][18][19] In tumor cells with HRD, PARPi trap PARP on DNA to block SSB repair, promoting the accumulation of fatal DSB and DNA damage and triggering cell death through the welldescribed mechanism of synthetic lethality. [19][20][21] Approximately 50% of all EOCs are characterized by HRD, mainly due to genomic alterations in HR genes, including but not limited to BRCA1/2, and this correlates with a higher sensitivity to platinum-based chemotherapy and PARPi. 22 Nevertheless, PARPi are less effective in cancer patients with proficient HR tumors.…”