Loss of Mig6 accelerates initiation and progression of mutant Epidermal growth factor receptor-driven lung adenocarcinoma
Menée à l'aide de modèles murins, cette étude met en évidence des mécanismes par lesquels le gène MIG6 exerce une fonction de suppresseur de tumeurs dans les adénocarcinomes du poumon présentant un gène EGFR muté
Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain drive lung adenocarcinoma. We have previously identified MIG6, an inhibitor of ERBB signaling and a potential tumor suppressor, as a target for phosphorylation by mutant EGFRs. Here we demonstrate that Mig6 is a tumor suppressor for the initiation and progression of mutant EGFR-driven lung adenocarcinoma in mouse models. Mutant EGFR-induced lung tumor formation was accelerated in Mig6-deficient mice, even with Mig6 haploinsufficiency. We demonstrate that constitutive phosphorylation of MIG6 at Y394/395 in EGFR-mutant human lung adenocarcinoma cell lines is associated with an increased interaction of MIG6 with mutant EGFR, which may stabilize EGFR protein. MIG6 also fails to promote mutant EGFR degradation. We propose a model whereby increased tyrosine phosphorylation of MIG6 decreases its capacity to inhibit mutant EGFR. Nonetheless, the residual inhibition is sufficient for Mig6 to delay mutant EGFR-driven tumor initiation and progression in mouse models.