Single nucleus RNA profiling reveals potential therapeutic vulnerabilities in sinonasal carcinomas.

Sinonasal undifferentiated carcinomas are rare, aggressive tumors with limited treatment options. Molecular subgroups defined by IDH2 mutations or SWI/SNF complex deficiencies have recently been recognized, but therapeutic implications remain unclear. We performed single-nucleus RNA sequencing on 12 FFPE tumors (six IDH2 mutated (IDH2mt), six SMARCA4 mutated (SMARCA4mt)), generating 59,612 nuclei. Malignant cells were identified by copy number inference, functionally characterized through gene set enrichment analysis, pathway and transcription factor activity analysis, and explored for druggable targets with spatial validation by immunohistochemistry and RNAscope. We identified 17 cell types and four malignant clusters with distinct programs: neuroendocrine-like (enriched in SMARCA4mt tumors), stress-adaptive with ECM remodeling, and EMT/TGF-β-driven. Target expression analysis revealed KIT overexpression in IDH2mt tumors and MET upregulation in SMARCA4mt tumors. The therapeutic relevance of KIT overexpression alone in absence of activating mutations remains uncertain, though treatment with multi-target kinase inhibitors with anti-KIT activity may warrant further investigation. MET overexpression may indicate potential relevance of MET-directed antibody-drug conjugate strategies. Both groups showed elevated CDK4 and DDR1 expression, nominating multi-target kinase inhibitors as potential options. Spatial expression uncovered collagenolysis-dependent DDR1 activation in tumor niches, highlighting DDR1 as a promising therapeutic vulnerability. Despite overlapping histology, IDH2mt and SMARCA4mt sinonasal carcinomas exhibit distinct transcriptional states and actionable dependencies. Our findings provide a framework for precision oncology in these rare tumors, supporting evaluation of KIT-, MET-, CDK4/6-, and DDR1-directed approaches.