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

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 replic...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Novel Approaches to Targeting DNA Repair: Oral Presentations - Invited Abstracts Source Type: research