Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor-Driven Lung Adenocarcinoma

Cancer Discovery
Tapan K MaityUdayan Guha

Abstract

Somatic mutations in the 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/Y395 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. This study demonstrates that MIG6 is a potent tumor suppressor for mutant EGFR-driven lung tumor initiation and progression in mice and provides a possible mechanism by which mutant EGFR can partially circumvent this tumor suppres...Continue Reading

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Citations

Mar 12, 2016·Computational Biology and Chemistry·Xiao-Dong YuChang-Jun Leng
Jun 28, 2016·Artificial Cells, Nanomedicine, and Biotechnology·Na Li, Meng Wei
Aug 19, 2015·Nature Structural & Molecular Biology·Eunyoung ParkMichael J Eck
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May 21, 2020·Arthritis Research & Therapy·Melina BelliniFrank Beier
Jul 23, 2020·Nature Communications·Jiao-Jiao YuZhuo-Wei Hu
May 6, 2015·Cancer Discovery·Evgeny Izumchenko, David Sidransky

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