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

Lineage transformation to squamous identity enables KRAS inhibitor resistance in mouse lung adenocarcinoma models, independent of KRAS/MAPK pathway reactivation.

• Why it matters: Understanding mechanisms of resistance to targeted therapies like KRAS inhibitors is crucial for improving treatment durability in lung adenocarcinoma, especially when resistance arises through lineage changes rather than pathway reactivation.
• What they did: The study used genetically engineered mouse models treated with KRAS inhibitors, combined with CRISPR techniques to induce squamous lineage transformation, examining genetic and transcriptional changes associated with resistance.
• The result: Squamous lineage transformation, driven by factors like ΔNp63 and Sox2, confers KRAS independence without reactivating KRAS/MAPK signaling, highlighting lineage plasticity as a key resistance mechanism.