Abstract POSTER-BIOL-1331: Nucleotide excision repair mutations confer sensitivity to platinum but not PARP-inhibitors in epithelial ovarian cancer

Abstract

Abstract The marked platinum sensitivity of epithelial ovarian cancer (EOC) is thought to be related to underlying defects in the homologous recombination (HR) DNA repair pathway, which are present in approximately 50% of tumors with high-grade serous histology. However, repair of platinum-induced DNA damage does not always involve the HR pathway. More than 90% of platinum-DNA lesions are intrastrand cross-links which are repaired by the nucleotide excision repair (NER) pathway. We curated the TCGA ovarian cancer dataset and identified 22 tumors (7%) with nonsynonymous or splice site NER gene mutations among the 316 sequenced high grade serous ovarian tumors. All NER mutations were mutually exclusive and 8 (36%) were accompanied by heterozygous loss of the respective NER gene. In 12 (55%) of the 22 cases, there were no concomitant HR alterations identified. In vitro functional evaluation of two NER mutations (ERCC6-Q524* and ERCC4-A583T), identified in patients with advanced stage tumors and extreme response to first-line platinum therapy, showed that both mutations conferred platinum, but not PARPi, or doxorubicin sensitivity, and did not affect HR activity. Interestingly, ERCC6-Q524* was not associated with heterozygous loss but sensitized cells to platinum in a dominant negative fashion. Our findings suggest a novel mechanism of platinum sensitivity in EOC that involves NER gene mutations, which may occur independently of HR alterations. Unlike tumors with defective HR, tumors harboring only NER mutations may be sensitive to platinum but not PARP inhibition. Dissociation of platinum and PARPi sensitivity in this setting may have important implications for PARPi trials for both HR-proficient and HR-deficient EOCs. Citation Format: Raphael Ceccaldi, Kevin O’Connor, Kent W. Mouw, Adam Y. Li, Ursula A. Matulonis, Alan D. D’Andrea, Panagiotis A. Konstantinopoulos. Nucleotide excision repair mutations confer sensitivity to platinum but not PARP-inhibitors in epithelial ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1331.