Alan D’Andrea, MD
Dana-Farber Cancer Institute
Novel mechanisms of PARP-inhibitor resistance in BRCA2-deficient ovarian and breast cancer
PARP inhibitors are a promising class of drugs for the treatment of ovarian cancers with defects in the BRCA1 or BRCA2 genes. However, drug resistance to PARP inhibitors poses a significant challenge for clinicians. Dr. D’Andrea’s group has recently shown that in cancer cells with BRCA2 mutations, PARP inhibitor resistance can be caused by decreased abundance of a protein called EZH2. Lower levels of EZH2 protect newly made DNA by reducing the recruitment of another protein called MUS81, that can chew up newly made DNA. Protection of newly made DNA has been shown by Dr. D’Andrea and others to lead to resistance to PARP inhibitors and cisplatin, first-line therapy for ovarian cancer. This study will allow Dr. D’Andrea to better understand how reduced expression of EZH2 leads to PARP inhibitor resistance and determine how common this phenomenon is in resistant ovarian cancer samples from patients. Understanding how PARP inhibitor resistance works is necessary to develop better therapies and to more effectively predict tumor response to treatment.