Abstract 1427: Co-alteration of the nucleosome remodeler, ARID1A with the PI3K-pathway genes: A signaling opportunity in ovarian cancers
Authors: Dey Nandini , Aske Jennifer C. , Thompson Ethan , Rojas-Espaillat Luis , Starks David , De Pradip 
Published: September 2020

Abstract
Objectives: We present mutations in the ARID1A gene and its co-occurrence with alterations of gene(s) of the PI3K pathway (GOP) in our clinical cohort of ovarian carcinomas (OC). We interrogated the signaling opportunity of the co-occurrence in tumorigenic transformation of OC.
Methods: A comprehensive genomic-profiling (FoundationOne) was performed in 90 samples from patients admitted to the Avera Center Institute, USA. The mechanistic study included epithelial endometrioid adenoC cell line A2780 and A2780Cis. CRISPR-Cas9 edited OVCAR3 cell line was used for an ARID1A-incompetent model. Algorithmically chosen drugs, single or in combination were tested for their effect on cell cycle, proliferation, apoptosis, 3D growth, and cellular signals.
Results: We recorded 87% metastatic and 11% adjuvant tumors with a predominant histological type of high grade serous (58%). A total of approximately 318 alterations in 100 genes was observed. Alterations (point mutation, frameshifts, and splice site) in the ARID1A was found in 8 patients whose tumors are predominantly clear cell carcinomas (6 out of 8). Interestingly none had alteration in germline BRCA1/2. All frameshift mutations were found in the adjuvant category while alterations in the metastatic category were more diverse. Alteration of GOP included PIK3CA, PIK3R1, AKT2, PTEN, AKT1, AKT3, MDM4, PIK3C2B, PIK3CB, TSC1, STK11, PPP2R1A, and FBXW7 with the most number of alterations in PIK3CA, PIK3R1, AKT2, PTEN genes. A heatmap showed that all patients with ARID1A alterations had alterations in at least one GOP. Treatment with PI3K inhibitor, copanlisib dose-dependently induced apoptosis both as a single agent and in combination with BMN673 in OC cells.
Conclusion: OC expressing alteration of ARID1A frequently exhibit a co-alteration in at least one GOP, and the co-alteration provide a unique signaling opportunity to test rational combination of pathway-targeted drugs in OC. Our study provides an insight into the mechanism of how a loss of a tumor suppressor gene, ARID1A co-operates with gain of function mutation(s) of an oncogenic pathway, the PI3K pathway.
Background: Nucleosome remodelers controls transcription of genes in human health and sickness by dynamic remodeling of human chromatin in a spatiotemporal manner. ARID1A, a core component of the mammalian SWI/SNF nucleosome remodeler complex, which interacts with DNA in a sequence-nonspecific way to regulate cellular processes, including proliferation and differentiation and hence reported to be involved in tumorigenesis (PMID: 25387058). The mutational (inactivating) status of ARID1A in a broad spectrum of gynecological neoplasms (PMID: 22009941) predominantly ovarian and endometrial cancers established its role as an epigenetic tumor suppressor (PMID: 23208470).
The mechanistic study included OC cell line A2780 (epithelial), established from an untreated patient with ovarian endometroid adenocarcinoma and an isogenic cis-platin resistant cell line, A2780Cis.
The results were being interrogated in the light of tumor cell signaling.
Citation Format: Nandini Dey, Jennifer C. Aske, Ethan Thompson, Luis Rojas-Espaillat, David Starks, Pradip De. Co-alteration of the nucleosome remodeler, ARID1A with the PI3K-pathway genes: A signaling opportunity in ovarian cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1427.