Putative Molecular Mechanism Contributing Azd6244 Resistance In Lung Cancer

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 …