NSCLC KRAS G12C MUTANT CELLS ARE DEPENDENT ON MUC1-C FOR RESISTANCE TO RAS(ON) INHIBITORS

Treatment of NSCLC KRAS G12C mutant tumors with targeted KRAS inhibitors, such as sotorasib and adagrasib, is invariably associated with the emergence of acquired resistance. The mechanisms responsible for resistance to these agents have largely remained unclear. We report that patients with NSCLC KRAS G12C tumors expressing increased levels of the MUC1 gene exhibit decreases in overall survival in response to sotorasib and adagrasib. In investigating the basis for this finding, we found that exposure of NSCLC KRAS G12C mutant cells to these agents induces expression of the oncogenic MUC1-C/M1C protein. Studies of RAS(ON)-resistant (RMC-R) cells further reveal upregulation of M1C chromatin levels in association with activation of the epithelial-mesenchymal transition (EMT). Mechanistically, M1C drives NF-kB p65-mediated induction of the ZEB1 EMT-TF. Furthermore, targeting M1C NF-kB ZEB1 signaling suppresses EMT and sotorasib resistance. Having identified this M1C dependence, we demonstrate that targeting M1C with an antibody-drug conjugate (ADC) is effective against sotorasib-resistant cells growing in vitro and as tumor xenografts. These findings identify M1C as a major effector of sotorasib resistance and as a target for ADC treatment of patients with refractory NSCLC KRAS G12C mutant tumors.