Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

Menée à l'aide notamment d'organoïdes et de modèles murins de cancer du poumon avec mutation KRASG12D et déficience ou non de LKB1, cette étude met en évidence le rôle de la transition adéno-épidermoïde dans la résistance aux inhibiteurs de KRAS

Résumé en anglais

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal