LKB1 is a master kinase that is mutated or underexpressed in 20-30% of non-small cell lung cancer (NSCLC) patient tumors. Because wild-type LKB1 functions as a sensor of energetic stress, the response to metabolic inhibition or nutrient depletion becomes dysregulated in LKB1-deficient cells. We have assessed the metabolic response to treatment of LKB1-deficient NSCLC cells with the clinically relevant EGFR inhibitor erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib treatment despite having wild-type EGFR. We have found that this enhanced response is due to mitochondrial dysfunction and altered energetic metabolism in LKB1-deficient cells, which prevents homestatic maintenance of ATP and reactive oxygen species (ROS) levels in response to erlotinib treatment. This subsequently results in reductions in mTOR signaling and cell growth, as well as activation of apoptosis. These findings will be important for designing targeted treatments for LKB1-deficient NSCLC patient tumors, which disrupt metabolic and signaling pathways known to regulate energy metabolism in these cells.
