Lineage identity governs oncogene dependence in mouse NSCLC models of KRAS inhibitor resistance.

Primary and acquired resistance to targeted therapy represent significant challenges to durable treatment responses in oncology. In lung adenocarcinoma, KRAS inhibitors are hampered by incomplete clinical responses and acquired resistance. Here we treated genetically engineered mouse models of Kras-driven lung adenocarcinoma with KRAS inhibitors to model these conditions. Initial treatment response was rapid but incomplete, with residual tumor burden transcriptionally resembling alveolar epithelial cells. With continued treatment, we invariably observed genetic Kras amplification as a resistance mechanism. To model oncogene-independent resistance, we used functional CRISPR approaches to promote squamous lineage transformation. We found that ∆Np63 was sufficient to transform alveolar organoids to a squamous state in vitro, conferring insensitivity to KRAS inhibition. In vivo, Nkx2-1 loss and/or ectopic Sox2 expression poised tumors for squamous lineage commitment. Squamous-transformed tumors did not exhibit evidence of KRAS/MAPK reactivation, underscoring the role for lineage transcription factors and histologic transformation in mediating KRAS independence.