Abstract 4265: Derivation and characterization of endometrial cancer cells resistant to phosphatidylinositol-3-kinase (PI3K) pathway inhibitors.

Abstract

Abstract Endometrial cancer remains the most common gynecologic malignancy in the United States with an estimated 43,000 cases annually. Limited options exist for patients with recurrent endometrial cancer after tumor progression following platinum/taxane combinations, and newer therapies are needed. Endometrial cancers have among the highest rates of oncogenic aberrations in the phosphatidylinositol-3-kinase (PI3K) pathway with frequencies approaching 75%, and clinical trials targeting components on the PI3K pathway are ongoing. Despite the clinical observation that many responses to PI3K inhibitors are short lived an understanding of the molecular mechanisms of resistance is lacking. We have derived endometrial cancer cell lines resistant to a panel of PI3K/AKT/mTOR inhibitors in clinical development in an effort to understand molecular mechanisms and signaling changes underlying resistance to PI3K-targeted therapy. All lines have previously undergone mutational analysis of the PI3K and RAS-ERK pathways. Representative compounds inhibiting each node in the canonical class I PI3K signaling cascade have been chosen. These agents have been synthesized base on the published structures and include a pan-p110 inhibitor, an allosteric AKT inhibitor, a dual p110-mTOR, and a MEK inhibitor. Using parallel high-throughput intracellular phospho-kinase and phospho-receptor tyrosine kinase (RTK) arrays for screening we have identified candidate common resistance mechanisms to inhibition of signaling nodes in the PI3K pathway. The phospho-screening approach has highlighted the interplay between PI3K/AKT/mTOR signaling and the Ras/Raf/MEK/ERK pathways in the development of resistance. We have begun to validate ERK upregulation as an activated escape pathway in patient samples from an AKT inhibitor clinical trial. Conserved resistance profiles may ultimately be used to define a subset of endometrial cancer patients unlikely to respond to PI3K/Akt/mTOR inhibitors and may inform more rational early phase combination strategies. Citation Format: Samuel J. Klempner, Andrea P. Myers, Jane Li, Gordon Mills, Lewis C. Cantley. Derivation and characterization of endometrial cancer cells resistant to phosphatidylinositol-3-kinase (PI3K) pathway inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4265. doi:10.1158/1538-7445.AM2013-4265