Abstract 30: Small molecule profiling uncovers the landscape of combinatorial PI3K inhibitor responses in HNSCC

Abstract

Abstract Recent sequencing studies of head and neck squamous cell carcinomas (HNSCCs) have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated oncogenic pathway in this cancer type. Although activating mutations or amplification in PIK3CA (the gene encoding the catalytic subunit of PI3K) are frequently observed in HNSCC, monotherapies targeting PI3K have shown limited clinical efficacy. We tested a panel of more than 20 patient-derived oral cavity squamous cell carcinoma (OCSCC) cell lines, which were profiled by Nimblegen V3 exome sequencing. Despite PIK3CA copy number amplification and/or mutations, we observed resistance to PI3K inhibitors in these models. Of six inhibitors tested, the only agents with marginal effects were alpha-isoform selective and pan-PI3K agents; these inhibitors, despite on-target and downstream activity, did not cause an appreciable reduction in cell viability when administered at submicromolar concentrations. We hypothesized that other oncogenic pathways, such as the Ras-MEK-ERK pathway, might still be functional in the presence of PI3K inhibitors and serve as compensatory mechanisms of resistance to these drugs. In order to more fully characterize other novel co-dependent pathway in PI3K inhibitor resistant HNSCC models, we have developed a high-throughput screening approach that utilizes a resazurin cell viability assay. This approach is an unbiased means of testing ~1400 inhibitors as monotherapies and in combination with alpha-isoform selective PI3K inhibitor HS-173 and pan-PI3K inhibitor BKM120 and has been utilized in several in vitro models of OCSCC to date. Testing of additional cellular models and validation of “hits” from this screen, which are drugs that are effective in combination but not as monotherapies, may identify additional resistance mechanisms and are currently ongoing. Developing a better understanding of these combination therapies and the patients in which they might be most effective may lead to improved prognosis for this disease. Citation Format: Nicole L. Michmerhuizen, Elizabeth Leonard, Micah Harris, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Jiang Hui, J. Chad Brenner. Small molecule profiling uncovers the landscape of combinatorial PI3K inhibitor responses in HNSCC [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 30.