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.

doi:10.64898/2025.12.02.691049

bioRxiv · 10.64898/2025.12.02.691049

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.

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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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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.. 2025-12-05. M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors. https://doi.org/10.64898/2025.12.02.691049

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