Abstract IA20: Therapeutic targeting of ARID1A mutation in ovarian cancer

Abstract

Abstract SWI/SNF chromatin remodeling complexes regulate gene transcription by changing chromatin structure through hydrolyzing ATP. Cancer genome sequencing found that mutations in genes encoding for the subunits of the SWI/SNF complexes collectively occur in ~20% of all human cancers. For example, saturation analysis of The Cancer Genome Atlas (TCGA) cancer mutational profile reveals that the ARID1A subunit of the SWI/SNF complex shows one of the highest mutation rates among epigenetic regulators. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas and 30% of ovarian endometrioid carcinomas. ARID1A mutation is a known genetic driver of ovarian cancer. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression. Loss of ARID1A correlates with late-stage disease and predicts early recurrence of ovarian clear cell carcinoma. Ovarian clear cell carcinoma ranks second as the cause of death from epithelial ovarian cancer and is associated with the worst prognosis among the major ovarian cancer subtypes when diagnosed at advanced stages. Additionally, for advanced-stage disease, there is currently no effective therapy. Here we will discuss emerging opportunities for therapeutic targeting of ARID1A mutation based on the genetic makeup of ARID1-mutated ovarian cancer with precision. They include synthetic lethality, the mutual exclusivity between ARID1A and TP53 mutations in ovarian cancer, and mechanism-guided combinatory approaches. Citation Format: Rugang Zhang. Therapeutic targeting of ARID1A mutation in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA20.