Abstract 3698: Hyperactive AKT pathway and reactivation of the MAPK/ERK pathway in melanoma cells resistant to dual BRAF and MEK inhibition

Abstract

Abstract In order to understand the mechanisms of resistance in melanoma cells treated with dual BRAF and MEK inhibitors, A375 and SK-Mel-28 cell lines, both harboring the BRAF V600E mutation, were treated with escalating doses of vemurafenib and cobimetinib to generate dual resistant lines. Resulting cells demonstrated 10 to 30 fold increase in resistance to the drug combination compared with the parental lines. The resistance phenotype could not be reversed by an ERK inhibitor. RNA sequencing and Western analyses revealed hyperactivation of the PI3K-AKT pathway in the A375 dual resistant cells. These cells may be re-sensitized with either a pan-PI3K inhibitor or PI3K/mTOR inhibitor. The SK-Mel-28 cells have constitutively active PI3K/AKT pathways at baseline and thus demonstrate reactivation of the MAP/ERK pathway in dual resistant cells. The therapeutic implications of these findings will be discussed. Citation Format: Victoria E. Wang, Frank McCormick, Jeffrey Settleman. Hyperactive AKT pathway and reactivation of the MAPK/ERK pathway in melanoma cells resistant to dual BRAF and MEK inhibition. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3698. doi:10.1158/1538-7445.AM2014-3698