mSWI/SNF complex inhibition sensitizes KRAS-mutant lung cancers to targeted therapies via epithelial-mesenchymal subversion - PubMed
4 hours ago
- #KRAS-mutant lung cancer
- #mSWI/SNF inhibition
- #therapy resistance
- KRAS-mutant lung cancers often develop resistance to targeted therapies, hindering treatment efficacy.
- Inhibition of the mSWI/SNF chromatin remodeling complex, specifically using SMARCA4/2 inhibitor FHD-286, can counter epithelial-mesenchymal transition (EMT)-mediated resistance.
- FHD-286 rewires mSWI/SNF chromatin activities to restore epithelial transcriptional programs, resensitizing drug-refractory models.
- Combining mSWI/SNF inhibition with KRAS inhibitors sensitizes non-G12C KRAS-mutant NSCLC cells to other KRAS-targeting drugs.
- FHD-286 and sotorasib combination shows potent anti-tumor efficacy in resistant and sensitive models, including organoids and patient-derived xenografts.
- mSWI/SNF inhibition is proposed as a combination strategy to enhance KRAS inhibitor efficacy and delay resistance emergence.