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

Lineage transformation to squamous identity confers KRAS inhibitor resistance in mouse lung adenocarcinoma models.

• Why it matters: Understanding mechanisms of resistance to targeted therapy is crucial for improving treatment durability in lung cancer.
• What they did: Researchers used genetically engineered mouse models of Kras-driven lung adenocarcinoma, applying KRAS inhibitors and CRISPR techniques to induce lineage changes and resistance.
• The result: Squamous lineage transformation, driven by ∆Np63, Nkx2-1 loss, or Sox2 expression, led to KRAS independence without KRAS/MAPK reactivation, highlighting lineage factors' role in resistance.