M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors
Takamori, S.; Haratake, N.; Bhattacharya, A.; Ozawa, H.; Shigeta, K.; Onishi, M.; Komiya, T.; Komatsuda, H.; Takenaka, T.; Yoshizumi, T.; Li, C.; Deng, J.; Hata, A. N.; Wong, K. K.; Long, M. D.; Kufe, D.
Show abstract
Treatment of NSCLC KRAS G12C mutant tumors with the allele-selective sotorasib inhibitor is invariably associated with acquired resistance. The MUC1-encoded oncogenic M1C protein is necessary for self-renewal of NSCLC KRAS mutant cells. We report that treatment of NSCLC KRAS G12C cells with sotorasib induces M1C expression by a STAT1-dependent pathway. In turn, M1C drives sotorasib resistance by NF-{kappa}B-mediated induction of the epithelial-mesenchymal transition (EMT). Targeting M1C(R)NF-{kappa}B signaling (i) suppresses EMT, and (ii) reverses sotorasib resistance. Of translational relevance, treatment with a M1C antibody-drug conjugate (ADC) is effective against sotorasib-resistant NSCLC KRAS G12C cell line and patient-derived tumor xenografts. Clinically, targeted treatment of patients with NSCLC KRAS G12C tumors overexpressing MUC1 associates with decreases in overall survival. These findings identify M1C as a key effector of sotorasib resistance and as a target for treatment of patients with refractory NSCLC KRAS G12C mutant tumors.
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