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M1C IS NECESSARY FOR DARAXONRASIB RESISTANCE OF NSCLC KRAS(G12C) MUTANT CELLS

Shinkichi Takamori1, Naoki Haratake1, Kentaro Nonaka1

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

Biorxiv : the Preprint Server for Biology
|July 8, 2026
PubMed
Abstract

Insights

The oncogenic protein M1C drives resistance to daraxonrasib in KRAS-mutant NSCLC by forming condensates with SHP2, activating STAT3 and NF-κB pathways. Targeting M1C can overcome this resistance, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance

Background:

  • Daraxonrasib is an effective RAS(ON) inhibitor for KRAS-mutant NSCLC.
  • Mechanisms of daraxonrasib resistance remain unclear.
  • The role of M1C in daraxonrasib resistance was previously unknown.

Purpose of the Study:

  • To investigate the role of M1C in acquired resistance to daraxonrasib in KRAS-mutant NSCLC.
  • To elucidate the molecular mechanisms by which M1C confers resistance.
  • To evaluate M1C as a potential therapeutic target for overcoming daraxonrasib resistance.

Main Methods:

  • Investigated M1C dependence in NSCLC cell lines (H358, H2122, MGH1112) with acquired daraxonrasib resistance.
  • Assessed SHP2, STAT1/3, and NF-κB activation, clonogenicity, and self-renewal capacity.
  • Targeted M1C, STAT3, and NF-κB pathways to assess reversal of resistance.

Main Results:

  • M1C is induced as a protective response in daraxonrasib-treated NSCLC KRAS(G12C) cells.
  • M1C forms novel membrane-associated biomolecular condensates with SHP2, driving resistance.
  • M1C integrates SHP2 activation with STAT3 and NF-κB signaling, including EMT.
  • Targeting M1C, STAT3, or NF-κB reversed daraxonrasib resistance.
  • M1C confers resistance to KRAS(G12C)-selective and RAS(ON) inhibitors via distinct mechanisms.

Conclusions:

  • M1C is essential for daraxonrasib tolerance in NSCLC.
  • M1C is a potential therapeutic target for NSCLC patients resistant to daraxonrasib.
  • Understanding M1C's role in resistance mechanisms is crucial for developing effective cancer therapies.
Keywords:
KRAS(G12C)M1CNSCLCdaraxonrasibresistance

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