Insights into significance of combined inhibition of MEK and m-TOR signalling output in KRAS mutant non-small-cell lung cancer

Background:We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR WT /ALK non-rearranged NSCLC cell lines.Methods:In a panel of KRAS M and KRAS WT NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively.Results:GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, P<10 -4). There was no significant difference in GI caused by maximal m-TOR compared with maximal m-TOR+MEK inhibition. However, GI caused by the combination was significantly greater in the KRAS M cell lines (79% vs 61%, P=0.017).Conclusions:m-TOR inhibition was more critical to GI than MEK inhibition in EGFR WT /ALK non-rearranged NSCLC cells. The combination of MEK and m-TOR inhibition was most effective in KRAS M cells.