Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma
Menée à l'aide de modèles murins, d'échantillons tumoraux et de xénogreffes dérivées de tumeurs issues de patients atteints d'un adénocarcinome du poumon, cette étude met en évidence un mécanisme par lequel la différenciation alvéolaire favorise la résistance des cellules cancéreuses à l'inhibition de KRAS
Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intratumoral heterogeneity and suggest that targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD.
Cancer Discovery , résumé, 2023