Abstract 322: Discovery of synergistic PI3K inhibitor combination therapies using high throughput approaches in HNSCC

Abstract

Abstract Recent head and neck squamous cell carcinoma (HNSCC) sequencing studies have identified the phosphatidylinositol 3-kinase (PI3K) pathway as the most frequently mutated, oncogenic pathway in this cancer type. Despite frequent activating mutation or amplification in PIK3CA (the gene encoding the catalytic subunit of PI3K), targeted PI3K inhibitors have shown limited clinical efficacy as monotherapies. To identify factors that might predict sensitivity and resistance to PI3K inhibitors, we tested a panel of more than 40 patient-derived HNSCC cell lines and observed varying sensitivity to PI3K inhibitors. While all cell lines were much more sensitive than fibroblasts to these drugs, responses varied widely; for pan-PI3K inhibitor BKM120, IC50 values ranged from 0.2 to 4.2 μM across the OSCC cell line panel. Responses to BKM120 do not correlate with PIK3CA mutation status copy number, RNA expression, p110α protein levels, and AKT phosphorylation at baseline and after inhibitor treatment, among other genetic or phenotypic features. In order to characterize potential mechanisms of PI3K inhibitor resistance in HNSCC, we have also developed and optimized an unbiased, high-throughput screening approach. We have used this assay to test ~1400 inhibitors as monotherapies and in combination with PI3K inhibitors HS-173 and BKM120 in ten HNSCC models. Our initial screening data suggested that combinations of PI3K inhibitors and ALK inhibitors are among the most synergistic in a subset of cell lines. We have evaluated the effects of these drug combinations on apoptosis, cell cycle, and downstream signaling in several in vitro HNSCC models, observing synergy in response to FDA-approved agents PI3K inhibitor pictilisib and ALK inhibitor brigatinib in various systems using a range of techniques. We next plan to expand these analyses to organoid and xenograft models to evaluate their effects in more clinically relevant settings. Future studies will also examine additional factors that may predict PI3K inhibitor responses and will seek to better understand promising combination treatments and advance them for effective use in HNSCC patients. Citation Format: Nicole Lynn Michmerhuizen, Elizabeth Leonard, Caitlin Heenan, Vivek Nair, Chloe Matovina, Micah Harris, Gabrielle Herbst, Daniel Kim, Amanda Bachand, Jingyi Zhai, Susan K. Foltin, Aditi Kulkarni, Thomas E. Carey, Carol R. Bradford, Hui Jiang, John C. Brenner. Discovery of synergistic PI3K inhibitor combination therapies using high throughput approaches in HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 322.