Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defense in KRAS-mutant lung cancer

Non-small cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumor suppressor LKB1 (KL NSCLC) is refractory to most therapies and has the worst predicted outcomes. Using human NSCLC metabolomics data, we uncovered upregulation of serine-glycine one carbon (SGOC) metabolism via serine hydroxymethyltransferase (SHMT) in KL NSCLC. A previous study in murine pancreatic tumor showed that the LKB1-AMPK axis inhibits SGOC which is necessary for DNA methylation. Here we report that in NSCLC, LKB1 impedes SGOC through SIK, not AMPK, and one carbon units are required for antioxidant defense, not epigenetic regulation. SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor SHIN2 enhanced the therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing ROS) in KL tumor growth in vivo. The data reveal tissue-of-origin as an important determinant of how cancers fulfill their metabolic requirements and provide insight into therapeutic strategies for KL NSCLC.