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

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.