Abstract A45: Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer

Abstract

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest. We hypothesized that dynamic changes in signaling, including adaptation and feedback, limit drug efficacy. Using a quantitative proteomics approach, we mapped dynamic changes in the kinome in response to various agents and identified signaling changes that correlate with drug sensitivity. Measurement of dynamics across a panel of breast cancer cell lines identified that maintenance of CDK4 and AURKA activity was associated with drug resistance. We tested whether incomplete inhibition of CDK4 or AURKA was a source of therapy failure and found that inhibition of either was sufficient to sensitize most breast cancer cells to PI3K, AKT, and mTOR inhibitors. In particular, drug combinations including the AURKA inhibitor MLN8237 were highly synergistic and induced apoptosis through enhanced suppression of mTOR signaling to S6 and 4E-BP1 leading to tumor regression in vivo. This approach identifies survival factors whose presence limits the efficacy of target therapy and suggests that Aurora kinase coinhibition could unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer. Citation Format: Hayley Donnella, James Webber, Kevan Shokat, Andrei Goga, John Gordan, Sourav Bandyopadhyay. Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A45.