MEK1/2 inhibition blocks development of autochthonous lung tumors induced by KRASG12D or BRAFV600E
Menée à l'aide d'un modèle murin génétiquement modifié, cette étude montre que l'inhibition de MEK1/2 permet de lutter contre la croissance de tumeurs pulmonaires induites par une mutation BRAFV600E ou KRASG12D
Genetically engineered mouse (GEM) models of lung tumorigenesis allow careful evaluation of lung tumor initiation, progression, and response to therapy. Using GEM models of oncogene-induced lung cancer, we demonstrate the striking similarity of the earliest stages of tumorigenesis induced by KRASG12D or BRAFV600E. Cre-mediated expression of KRASG12D or BRAFV600E in the lung epithelium of adult mice initially elicited benign lung tumors comprising cuboidal epithelial cells expressing markers of alveolar pneumocytes. Strikingly, in a head-to-head comparison, oncogenic BRAFV600E elicited many more such benign tumors and did so more rapidly than KRASG12D. However, despite differences in the efficiency of benign tumor induction, only mice with lung epithelium expression of KRASG12D developed malignant non-small-cell lung adenocarcinomas. Pharmacologic inhibition of MEK1/2 combined with in vivo imaging demonstrated that initiation and maintenance of both BRAFV600E- or KRASG12D-induced lung tumors was dependent on MEK→ERK signaling. Although the tumors dramatically regressed in response to MEK1/2 inhibition, they re-grew following cessation of drug treatment. Together, our findings demonstrate that RAF→MEK→ERK signaling is both necessary and sufficient for KRASG12D-induced benign lung tumorigenesis in GEM models. The data also emphasize the ability of KRASG12D to promote malignant lung cancer progression compared with oncogenic BRAFV600E.