Abstract B37: Mechanisms of acquired resistance to the PI3K inhibitor GDC-0941 in breast cancer cell lines

Abstract

Abstract Alterations of the phosphoinositide-3 kinase (PI3K)/Akt signaling pathway occur broadly in cancer via multiple mechanisms including mutation of the PIK3CA gene or loss of the tumor suppressor PTEN. The dysregulation of this pathway has been implicated in tumor initiation, cell growth and survival, invasion and angiogenesis, thus, PI3K is a promising therapeutic target for cancer. There are several PI3K inhibitors in clinical trials and the current study was intended to investigate preclinical mechanisms of acquired resistance to GDC-0941, a class I selective PI3K inhibitor. GDC-0941 resistant pools and clones were generated in both EVSA-T and HCC-1954 breast cancer cell lines by treating cells with increasing concentrations of drug. We found that resistant clones from both lines demonstrated marked increase of downstream PI3K pathway signaling and upregulation of the MAPK pathway, through two different mechanisms. In HCC-1954, autocrine signaling to EGFR was observed in the resistant clones and resulted in increased dependency on the downstream factor c-Myc. EVSA-T clones with acquired resistance to GDC-0941 had elevated HER2 copy number and protein expression levels. A corresponding increase in phosphorylation of HER2 binding partner ErbB3 was also discovered in the EVSA-T resistance cells. In both cases sensitivity to PI3K inhibition was restored by blocking the activated upstream receptor tyrosine kinase, EGFR for HCC-1954 and HER2 for EVSA-T. Additionally both models were re-sensitized to GDC-0941 by blocking downstream signaling of the MAPK pathway. These preclinical data may provide rationale for combination therapy with PI3K inhibitors in the clinic. Citation Format: Kyle A. Edgar, Ling Hwu, Kimberly Walter, Mark Lackner, Lori S. Friedman, Jeffrey J. Wallin. Mechanisms of acquired resistance to the PI3K inhibitor GDC-0941 in breast cancer cell lines. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr B37.