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Loss of MIG6 Accelerates Initiation and Progression of Mutant Epidermal Growth Factor Receptor-Driven Lung
Tapan K Maity1, Abhilash Venugopalan1, Ilona Linnoila2
1Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Unlabelled:
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.
Significance:
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 suppressor in human lung adenocarcinoma.
Insights
Mi-6 (MIG6) acts as a tumor suppressor in EGFR-mutant lung cancer. Its phosphorylation by mutant EGFR impairs its function, but residual inhibition still delays tumor growth in mouse models.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Somatic mutations in the Epidermal Growth Factor Receptor (EGFR) kinase domain are key drivers of lung adenocarcinoma.
- Mi-6 (MIG6) is an inhibitor of ERBB signaling and a potential tumor suppressor, previously identified as a phosphorylation target of mutant EGFRs.
Purpose of the Study:
- To investigate the role of Mi-6 (MIG6) as a tumor suppressor in the initiation and progression of mutant EGFR-driven lung adenocarcinoma.
- To elucidate the mechanism by which mutant EGFR may overcome Mi-6 (MIG6) tumor suppressor activity.
Main Methods:
- Utilized mouse models of mutant EGFR-driven lung adenocarcinoma.
- Examined Mi-6 (MIG6) phosphorylation status and interaction with mutant EGFR in human lung adenocarcinoma cell lines.
- Assessed the impact of Mig6 deficiency and haploinsufficiency on tumor formation and progression.
Main Results:
- Mig6 deficiency accelerated tumor formation in mutant EGFR-driven lung cancer mouse models, even with haploinsufficiency.
- Constitutive phosphorylation of Mi-6 (MIG6) at Y394/Y395 in EGFR-mutant cells correlated with increased interaction with mutant EGFR, potentially stabilizing it.
- Mi-6 (MIG6) failed to promote mutant EGFR degradation in this context.
Conclusions:
- Mi-6 (MIG6) is a potent tumor suppressor in mutant EGFR-driven lung tumor initiation and progression in mice.
- Increased tyrosine phosphorylation of Mi-6 (MIG6) by mutant EGFR may decrease its inhibitory capacity, providing a mechanism for partial circumvention in human lung adenocarcinoma.
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