Signaling Algorithm Based On Ras-Raf And Cell-Cycle Pathways' Alterations In Precision Medicine: Rational Combination Of Drugs In Ovarian Carcinoma

Introduction: Characteristic genetic alterations in ovarian cancers cause diverse upregulation of several oncogenic signal transduction pathways. Upregulation of oncogenic signaling has well-defined functional consequences in tumor cell phenotypes and thus determines therapeutic sensitivities of anticancer drugs. A therapeutic strategy can be developed by merging the (1) information about genetic alterations from a patient’s tumor with (2) an in-depth knowledge of cell signaling pathways pertaining to tumorigenesis. Aim: In our study, we interrogated the genomic alterations of the RAS and the cell cycle pathways to generate an algorithm for rational combinations of drugs in ovarian carcinoma. Methods: We analyzed genomic alterations (FoundationOne) of 90 tumor samples from 75 consecutive ovarian cancer patients who were seen in our Avera Center for Precision Oncology from February 2014 through June 2017. Tumors were characterized based on germline status for BRCA1/2, histologic types, stages, and specimen sites. Results: We recorded 87% metastatic and 11% adjuvant tumors with a predominant histologic type of high-grade serous (58%). We observed a total of 100 gene alterations in these tumors. Alterations in TP53 and MYC represented 72% and 25% of tumors, respectively. Within 90 tumors, 21% tumors exhibited an alteration in BRCA1/2 in either somatic or germline (15%). The genomic changes in FoundationOne results were resolved into different oncogenic signaling pathways including the RAS and cell cycle pathways. Seven genes of the RAS pathway were altered in 33% of the tumors including NF1u003e u003eRASu003eMAP3K1u003eNF2u003eBRAFu003eMAP2K4u003eNRAS. A total of 10 cell-cycle genes were altered in 90 tumors. Excluding TP53 and MYC alterations, the other major alterations were found in CCNE1 and CDKN2A/B genes. In cell line-based models (CDKN2A mutated SK-O-V3, RAF mutated A2780, and KRAS mutated OVK18), we studied the effect of trametinib (MEK1/2 inhibitor) and palbociclib/ribociclib (CDK4/6 inhibitor), single or in combination on proliferation, cell cycle, and apoptosis. Analyzing the composite alterations of the RAS pathway and the cell cycle pathway genes in individual patients, we observed that 20-24% tumors had coalterations of the RAS pathway genes and the cell cycle pathway genes. Importantly, all tumors with coalterations were found to be metastatic. Conclusion: Plotting the in-depth information about genetic coalterations of the RAS pathway and the cell cycle pathway genes from the tumors on the signaling landscape is a useful tool to crack the code for improved treatment options. A mechanistic evaluation is being carried out using a rational combination of drugs, trametinib and palbociclib/ribociclib in TP53 WT (A2780) and TP53 mutated (SK-OV3, OVK18) ovarian cancer cell lines, the result of which will be presented at the meeting. Citation Format: Nandini Dey, Casey Williams, Kirstin Williams, Jessica Klein, Jennifer H. Carlson, David Starks, Luis Rojas, Pradip De, Brian Leyland-Jones. Signaling algorithm based on RAS-RAF and cell-cycle pathways’ alterations in precision medicine: rational combination of drugs in ovarian carcinoma [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 B093.