Adeno-to-squamous transition drives resistance to KRAS inhibition inLKB1mutant lung cancer

Abstract

SummaryKRASG12Cinhibitors including adagrasib and sortorasib have shown clinical promise in targetingKRASG12C-mutated lung cancers, however, most patients eventually develop drug resistance. In lung adenocarcinoma patients with co-occurringKRASG12CandSTK11/LKB1mutations, we found a high squamous gene signature at baseline significantly correlated with poor adagrasib response. Through integrative studies ofLkb1-deficientKRASG12CandKrasG12Dlung cancer mouse models and/or organoids treated with KRAS inhibitors, we found tumor cells invoked a lineage plasticity program: adeno-to-squamous transition (AST) that mediated resistance to KRAS inhibition. Transcriptomic and epigenomic analyses revealed ΔNp63 drives AST and modulates response to KRAS inhibition. We identified an intermediate high-plasticity cell state with distinct gene expression program marked byKrt6aupregulation. Notably, higherKRT6Aexpression at baseline correlated with shorter overall survival inKRAS-mutant patients receiving adagrasib. These data support the role of AST in KRAS inhibitor resistance and provide predictive biomarker for KRAS-targeted therapies in lung cancer.