Abstract 721: Putative molecular mechanism contributing AZD6244 resistance in lung cancer

Abstract

Abstract The K-ras proto-oncogene is mutated in about 10-30% of non-small cell lung cancer, and these mutations are responsible for constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway, Raf/MEK/ERK. Therefore, several MEK inhibitors are currently under clinical trials to target K-Ras mutant lung cancer. AZD6244 (ARRY-142886) is an orally active and selective inhibitor that specifically targets MEK. We investigated the effect of AZD6244 on NSCLC cell lines to further understand the detailed molecular mechanism contributing to the sensitivity to this drug. Interestingly, two NSCLC cell lines, which have previously been reported as AZD6244-sensitive, exhibited a differential response to MEK inhibition by AZD6244. Specifically, long-term treatment by this drug eventually induced resistance in one of the two cell lines. We analyzed protein expression profile of the Bcl-2 family members which we hypothesized might play a role in the resistance to AZD6244 treatment. We found that while Bim appears to be stabilized in both apoptosis-resistant and -sensitive lung cancer cells, MCl-1 expression is increased in apoptosis-resistant lung cancer cells, suggesting that the increase in anti-apoptotic MCl-1 expression likely contributes to resistance under long-term AZD6244 treatment. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 721. doi:10.1158/1538-7445.AM2011-721