Lineage identity governs oncogene dependence in murine NSCLC models of KRAS inhibitor resistance [ATAC-Seq]

In lung cancer and other cancer types, allele- specific and pan-KRAS inhibitors offer new promise, but these are hampered by incomplete responses as well as genetic and non-genetic mechanisms of acquired resistance. To model these mechanisms, we treat genetically engineered mouse models of KrasG12C-driven lung cancer with sotorasib, a KRASG12C inhibitor, until the emergence of drug resistance.

The initial response to sotorasib was rapid, but incomplete. Residual tumor burden transcriptionally resembled the alveolar type II cell, phenocopying residual disease signatures identified in patients treated with EGFR inhibitors. After continued sotorasib treatment, we observed diverse mechanisms of drug resistance in vivo, including genetic MAPK reactivation and lineage transformation from adenocarcinoma to squamous histology.