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Cited by 73Lung Cancer Treatments and MutationsHER2/EGFR in Cancer ResearchLung Cancer Research Studies

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

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Maity, Tapan K., Venugopalan, Abhilash, Linnoila, Ilona, Cultraro, Constance M., Giannakou, Andreas, Nemati, Roxanne, Zhang, Xu, Webster, Joshua D. +9 more·2015·Cancer Discovery
DOI 10.1158/2159-8290.cd-14-0750PMC PMC4560174

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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. 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. Cancer Discov; 5(5); 534–49. ©2015 AACR. See related commentary by Izumchenko and Sidransky, p. 472. This article is highlighted in the In This Issue feature, p. 453

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Authors
Maity, T. K., Venugopalan, A., Linnoila, I., Cultraro, C. M., Giannakou, A., Nemati, R., Zhang, X., Webster, J. D., Ritt, D., Ghosal, S., Hoschuetzky, H., Simpson, R. M., Biswas, R., Politi, K., Morrison, D. K., Varmus, H. E., & Guha, U.
Affiliations
  • National Cancer Institute (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • 6nanoTools, Teningen, Germany.
  • 4Laboratory of Cancer Biology and Genetics, NCI, Bethesda, Maryland.
Corresponding author
Guha, Udayan
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2015-05-01
Volume
5
Issue
5
Pages
534-549
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-14-0750
PMC
PMC4560174
OpenAlex
W2147626375
Cited by
73
References
8
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 11 · 2022: 4 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 3 · 2017: 9 · 2016: 8 · 2015: 5
FWCI
6.58
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (ZIABC011259, P01CA129243, ZIABC011412, K99CA140792)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
Keywords
MIG6, mutant EGFR, lung adenocarcinoma, tumor suppressor, EGFR tyrosine phosphorylation, ErbB signaling, protein stability, EGFR degradation, tumor initiation and progression, mouse model
MeSH terms
Adenocarcinoma of Lung, Adenocarcinoma, Animals, Cell Transformation, Neoplastic, Humans, Lung Neoplasms, Mice, Transgenic, Mutation, Phosphorylation, Signal Transduction, Gene Expression, Gene Deletion, Mice, Knockout, Disease Progression, Mitogen-Activated Protein Kinases, Tumor Suppressor Proteins, Proteomics, Cell Line, Tumor, Protein Kinase Inhibitors, Adaptor Proteins, Signal Transducing, Mice, ErbB Receptors

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