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M1C is a druggable target for NSCLC KRAS G12C mutant tumors resistant to KRAS inhibitors

Shinkichi Takamori1, Naoki Haratake1,2, Atrayee Bhattacharya1,3

  • 1Department of Medical Oncology Dana-Farber Cancer Institute Harvard Medical School, Boston, MA, USA.

Oncogene
|August 5, 2026
PubMed

Insights

The oncogenic M1C protein drives resistance to KRAS G12C inhibitors like sotorasib in non-small cell lung cancer (NSCLC). Targeting M1C reverses resistance and shows promise for refractory NSCLC KRAS G12C mutant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Non-small cell lung cancer (NSCLC) with KRAS G12C mutations often develops resistance to targeted therapies like sotorasib and adagrasib.
  • The MUC1-encoded oncogenic M1C protein is crucial for the self-renewal of NSCLC KRAS mutant cells.

Purpose of the Study:

  • To investigate the role of M1C in acquired resistance to KRAS G12C inhibitors in NSCLC.
  • To explore M1C as a potential therapeutic target for overcoming treatment resistance.

Main Methods:

  • Analysis of M1C expression in NSCLC KRAS G12C cells treated with sotorasib.
  • Investigating the STAT1 and NF-κB signaling pathways involved in M1C-mediated resistance.
  • Evaluating the efficacy of targeting M1C-NF-κB signaling and M1C antibody-drug conjugates (ADCs) in preclinical models.
  • Correlating MUC1 expression with patient survival outcomes in NSCLC treated with KRAS G12C inhibitors.

Main Results:

  • Sotorasib treatment induces M1C expression via a STAT1-dependent pathway in NSCLC KRAS G12C cells.
  • M1C promotes resistance by inducing epithelial-mesenchymal transition (EMT) and a mucinous gene program through NF-κB signaling.
  • Targeting M1C→NF-κB signaling suppressed EMT and mucin genes, reversing sotorasib resistance.
  • An M1C ADC demonstrated efficacy against resistant NSCLC cell lines and patient-derived xenografts.
  • MUC1 overexpression in patients with NSCLC KRAS G12C tumors treated with sotorasib/adagrasib correlated with decreased overall survival.

Conclusions:

  • M1C is identified as a key mediator of acquired resistance to KRAS G12C inhibitors in NSCLC.
  • Targeting M1C and its downstream signaling pathways represents a promising therapeutic strategy for refractory NSCLC KRAS G12C mutant tumors.

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