Abstract B092: Molecular aberrations of the PI3K-AKT-mTORC1/C2 pathway in ovarian cancers: a strategy for targeted therapy
Authors: De Pradip , Williams Casey , Rojas Luis , Williams Kirstin , Klein Jessica , Starks David , Carlson Jennifer H. , Dey Nandini , Leyland-Jones Brian 
Published: August 2018

Abstract
Background: Ovarian cancer is the most lethal gynecologic cancer worldwide since most patients are diagnosed at an advanced stage of the disease. Genetic alterations of the PI3K-AKT-mTORC1/C2 pathway in ovarian cancer (OC) are characteristically abundant and diverse. These alterations hyperactivate oncogenic signals that have well-defined functional consequences on oncogenesis and thus determine the therapeutic response to pathway-specific drugs. Purpose: We have conducted comprehensive genomic profiling of ovarian tumors from our patients. Based on our examination of genomic alterations in tumors from ovarian cancer patients at Avera Cancer Institute, SD, we have studied antitumor effects of pathway-specific inhibitor(s) either alone or in combination using cell line-based model (PIK3CA mutated, HER2 amplified SKOV3, PIK3CA, PTEN and RAF mutated, A2780, TP53, PTEN, KRAS and ARID1A mutated, OVK18, and TP53 mutated OVCAR3 cells). Methods: Comprehensive genomic profiling [FoundationOne] from 75 OC patients (90 tumor samples, neoadjuvant 1, adjuvant 10, and metastatic 79) (February 2014 through June 2017) was analyzed. We also evaluated the distribution of mutations in cell free DNA via digital NGS using the FoundationAct and Guardant 360 panel. Results: In total, 100 genes were altered in ovarian tumors, among which the most frequent genetic alterations are observed in TP53 (72%). The PI3K-AKT-mTORC1/C2 pathway-specific genes were altered in 35.5% of ovarian tumors. The most notable alterations are PIK3CA (9 tumors), PIK3R1 (8 tumors), AKT2 (5 tumors), and PTEN (4 tumors). BRCA1/BRCA2 was altered in 21% of patients (15% germline). We studied the antitumor efficacy of (1) isoform-specific PI3K inhibitor (alpha or beta), (2) an allosteric mTOR inhibitor, (3) kinase inhibitor of mTOR, and (4) a combination of alpha-specific PI3K inhibitor plus mTOR inhibitor using ovarian cancer cell lines. Data showed that a combined effect of isoform-specific PI3K inhibitor plus mTOR kinase inhibitor or taxol plus PI3K pathway-specific inhibitor was more effective than a single inhibitor in controlling proliferative and apoptotic signals leading to cell cycle arrest. Conclusion: Our preclinical data provide a conceptual framework for the use of pathway-specific inhibitor(s) when matched with alteration of the pathway-specific genes in ovarian tumors. This strategy warrants further clinical investigation.
Citation Format: Pradip De, Casey Williams, Luis Rojas, Kirstin Williams, Jessica Klein, David Starks, Jennifer H. Carlson, Nandini Dey, Brian Leyland-Jones. Molecular aberrations of the PI3K-AKT-mTORC1/C2 pathway in ovarian cancers: a strategy for targeted therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B092.