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

Gentile, C.; Feng, W. W.; Lenahan, S. M.; Ying, A. W.; Card, D. C.; Wu, F. T. H.; Pham, N.-A.; Radulovich, N.; Cao, P. M.; Hueniken, K.; Li, Q.; Tsao, M.-S.; Kulesza, J.; Hinkley, M. M.; Liao, L.; Tsai, J. A. < A.; Kohler, J.; Facchinetti, F.; Li, J.; Weston, C.; Locquet, M.-A.; Ngo, K.; Gokhale, P. C.; Sacher, A. G.; Janne, P. A.; Kadoch, C.

doi:10.64898/2026.02.27.708377

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bioRxiv · 10.64898/2026.02.27.708377

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

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Abstract

Targeted therapies for KRAS-mutant non-small lung cancer (NSCLC) have shown promising clinical results, however, incomplete tumoral responses and the inevitable emergence of therapeutic resistance remain critical challenges. Here we identify mSWI/SNF chromatin remodeling complexes as critical determinants of (EMT)-mediated KRAS inhibitor inefficacy and resistance in KRAS G12C lung cancers. Treatment with the clinical-grade SMARCA4/2 inhibitor, FHD-286, dampens EMT-mediated acquired resistance in drug-responsive models and similarly resensitizes drug-refractory models by rewiring mSWI/SNF chromatin localization and activities that modulate epithelial transcriptional programs and cell state. Further, synergistic mSWI/SNF and KRAS inhibitor combination treatment sensitizes non-G12C KRAS-mutant NSCLC cells to pan-RAS and G12D-specific inhibitors. Finally, FHD-286 and sotorasib combination treatment results in potent anti-tumor efficacy in both G12Ci-resistant and - sensitive organoid models and in vivo patient-derived xenograft (PDX) systems. These data nominate mSWI/SNF inhibition as a combination strategy to improve KRAS inhibitor efficacy, response duration, and to mitigate emergence of resistance.

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Gentile, C., Feng, W. W., Lenahan, S. M., Ying, A. W., Card, D. C., Wu, F. T. H., Pham, N.-A., Radulovich, N., Cao, P. M., Hueniken, K., Li, Q., Tsao, M.-S., Kulesza, J., Hinkley, M. M., Liao, L., Tsai, J. A. < A., Kohler, J., Facchinetti, F., Li, J., Weston, C., Locquet, M.-A., Ngo, K., Gokhale, P. C., Sacher, A. G., Janne, P. A., Kadoch, C.. 2026-03-01. mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion. https://doi.org/10.64898/2026.02.27.708377

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