Abstract C102: Identify novel pathways conferring PARP inhibitor resistance in BRCA-associated breast and ovarian cancer.

Abstract

Abstract Inhibitors of poly(ADP-ribose) polymerase (PARP) enzymes hold great promise in treating BRCA1/2 associated breast and ovarian cancers, which have profound homologous recombination (HR) defect. However, not all BRCA1/2 patients respond to PARP inhibitor treatment, and the majority of the responders eventually relapsed. Little is known about the resistance mechanisms that are clinical relevant. We recently developed a highly versatile insertional mutagenesis system, using transposons to insert a CMV promoter randomly into the genome and thereby activate nearby genes. We constructed genome-wide insertional libraries using both human and mouse BRCA1-deficient cancer cell lines. When these mutated cells were treated with the PARP inhibitor, resistant colonies formed at extremely low frequency. Resistant colonies were re-grown and maintained in drug-free medium for extended period of time and robust resistance was retained. Insertion sites for these colonies were then determined, many of which are near genes whose alteration in expression can up-regulate activities of MEK/ERK pathway or PI3K/AKT pathway. Next we hope to investigate the resistance mechanism. We hypothesize that resistance is mediated via decreased DNA damage, improved DNA repair, or increase in general survival pathway after PARP inhibitor treatment. We have access to tumor specimens from a recently-completed clinical trial using ABT-888 in combination with temozolomide in a BRCA1/2 carrier-enriched population. The expression level and mutational status of these genes will be surveyed and correlated with clinical response. Finally based on the insight gained from aforementioned mechanism study, we hope to find inhibitors that specifically target the resistance mechanism; by combining this inhibitor with PARP inhibitor, we could develop effective therapy to treat the subset of patients resistant to PARP inhibitor. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C102. Citation Format: Lei He, Li Chen, Saranya Ramakrishnan, Kristine Torres-Lockhart, Leif Ellisen. Identify novel pathways conferring PARP inhibitor resistance in BRCA-associated breast and ovarian cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C102.