PARP Inhibitor Resistance and Acquired Vulnerability
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. The most commonly altered HRR genes are BRCA1 and BRCA2, followed by other Fanconi Anemia Genes. Loss of HRR causes genomic instability, hyperdependence on alternative DNA repair mechanisms, and enhanced sensitivity to PARP-inhibitors (PARPi) through the mechanism of synthetic lethality. PARP inhibitor resistance has emerged as a vexing clinical problem for the treatment of BRCA1/2 deficient tumors. The most prevalent mechanism of PARPi resistance is secondary events that cancel the original HRR alteration and restore HRR proficiency. PARPi resistance also develops without restoration of HRR proficiency through enhanced replication fork (RF) stabilization. We have recently made the surprising observation that BRCA2-deficient tumor cells can stabilize their replication forks and become resistant to PARPi by downregulating the expression of various methyltransferases, such as MLL3/4 and EZH2. Other new mechanisms of PARPi resistance will be discussed. A molecular understanding of PARP inhibitor resistance mechanisms may allow the generation of a new class of drugs, or a re-purposing of existing drugs, which may reverse this resistance and extend the use of PARP inhibitors to more tumor types.
Director: Center for DNA Damage and Repair