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mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal

Claudia Gentile1,2, William W Feng3, Sean M Lenahan3

  • 1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA 02215.

Biorxiv : the Preprint Server for Biology
|May 13, 2026
PubMed

Insights

Targeting KRAS-mutant lung cancer faces resistance. Inhibiting mSWI/SNF chromatin remodelers with FHD-286 resensitizes tumors to KRAS inhibitors, improving treatment efficacy and duration.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • KRAS-mutant non-small cell lung cancer (NSCLC) targeted therapies show promise but face challenges with incomplete responses and resistance.
  • The epithelial-mesenchymal transition (EMT) plays a role in KRAS inhibitor inefficacy and acquired resistance.

Purpose of the Study:

  • To investigate the role of mSWI/SNF chromatin remodeling complexes in KRAS inhibitor resistance in NSCLC.
  • To evaluate mSWI/SNF inhibition as a strategy to overcome resistance and improve therapeutic outcomes.

Main Methods:

  • Utilized a clinical-grade SMARCA4/2 inhibitor (FHD-286) in preclinical models of KRAS G12C lung cancer.
  • Assessed the impact of FHD-286 on EMT-mediated resistance, chromatin remodeling, and epithelial transcriptional programs.
  • Investigated combination treatments with KRAS inhibitors in various KRAS-mutant NSCLC models, including organoids and patient-derived xenografts (PDX).

Main Results:

  • FHD-286 treatment dampened EMT-mediated acquired resistance in responsive models and resensitized refractory models.
  • mSWI/SNF inhibition rewired chromatin localization and activities, modulating epithelial programs and cell state.
  • Combination therapy of mSWI/SNF and KRAS inhibitors sensitized non-G12C KRAS-mutant NSCLC cells to pan-RAS and G12D-specific inhibitors.
  • Combined FHD-286 and sotorasib demonstrated potent anti-tumor efficacy in resistant and sensitive models, including PDX systems.

Conclusions:

  • mSWI/SNF chromatin remodeling complexes are critical determinants of EMT-mediated KRAS inhibitor resistance in NSCLC.
  • mSWI/SNF inhibition represents a viable combination strategy to enhance KRAS inhibitor efficacy, prolong response duration, and overcome therapeutic resistance.

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