Abstract IA25: Novel mechanisms of PARP-inhibitor resistance in tumors with defects in the Fanconi Anemia/BRCA pathway

Abstract

Abstract Large-scale genomic studies have demonstrated that approximately 50% of high-grade serous ovarian cancers (HGSOCs) harbor genetic and epigenetic alterations in homologous recombination repair (HRR) pathway genes. HRR alterations have also been identified, albeit less frequently, in other human malignancies including triple negative breast, prostate, and pancreatic cancers. The most commonly altered HRR genes are BRCA1 and BRCA2 followed by other Fanconi Anemia (FA) genes (e.g. PALB2, FANCA, FANCI, FANCL, and FANCC), core RAD genes (e.g. RAD50, RAD51, RAD51C, and RAD54L) and DNA damage response genes involved in HRR, such as ATM, ATR, CHEK1, and CHEK2. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to certain types of DNA-damaging chemotherapy such as platinum analogues and topoisomerase inhibitors. HRR deficient tumors are also exquisitely sensitive to PARP-inhibitors (PARPis) which exhibit synthetic lethality to cells with defective HRR. This synthetic lethal interaction is being exploited therapeutically in diverse clinical contexts and most notably in ovarian cancer where the PARPi olaparib is FDA approved for use in patients with germline BRCA1/2 mutations who have progressed through at least 3 prior lines of therapy. The efficacy of PARPis against HRR deficient cells can be explained by various mechanisms including inhibition of base excision repair (BER), trapping of PARP-DNA complexes at the replication fork, enhancement of toxic non-homologous end joining in PARP1-deficient cells, and inhibition of PARP1/Polθ-mediated alternative end joining (alt-EJ). Underlying HRR deficiency is important for the cytotoxicity of PARPis and this is highlighted by the fact that the most prevalent mechanism of PARPi resistance is secondary genetic and epigenetic events that cancel the original HRR alteration and restore HRR proficiency. However, PARPi resistance may still develop without restoration of HR proficiency via reduced uptake and increased efflux of the drugs or via disruption of multiple proteins such as PTIP or CHD4 that leads to replication fork protection. Importantly, this latter mechanism-namely, the restoration of RF stability- appears to be a highly prevalent mechanism of PARP inhibitor resistance in vitro and in vivo, particularly in tumor cells with an underlying BRCA2 deficiency. Due to their underlying deficiency in BRCA2 and inability to generate RAD51 nucleofilaments, these tumor cells are unable to restore HRR mechanisms. Instead, these cells acquire PARP inhibitor resistance by limiting the nucleolytic degradation of their stalled replication forks. In my presentation, I will discuss new mechanisms of RF nucleolytic degradation and novel mechanisms by which tumors can avoid this degradation and acquire PARP inhibitor resistance. A molecular understanding PARP inhibitor resistance mechanisms is important, since it may allow the generation of a new class of drugs, or a repurposing of existing drugs, which may reverse this resistance and extend the use of PARP inhibitors to more tumor types. Citation Format: Alan D. D'Andrea. Novel mechanisms of PARP-inhibitor resistance in tumors with defects in the Fanconi Anemia/BRCA pathway [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA25.