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


CONCLUSIONS
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.
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Tapan K
TK
Maity
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Abhilash
A
Venugopalan
Cell and Cancer Biology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Ilona
I
Linnoila
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Constance M
CM
Cultraro
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Andreas
A
Giannakou
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Roxanne
R
Nemati
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Xu
X
Zhang
Laboratory of Cancer Biology and Genetics, NCI, Bethesda, Maryland.
Joshua D
JD
Webster
Laboratory of Cell and Developmental Signaling, NCI, Frederick, Maryland.
Daniel
D
Ritt
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Sarani
S
Ghosal
nanoTools, Teningen, Germany.
Heinz
H
Hoschuetzky
Laboratory of Cancer Biology and Genetics, NCI, Bethesda, Maryland.
R Mark
RM
Simpson
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland.
Romi
R
Biswas
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Katerina
K
Politi
Laboratory of Cell and Developmental Signaling, NCI, Frederick, Maryland.
Deborah K
DK
Morrison
Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Harold E
HE
Varmus
Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, NCI, Bethesda, Maryland. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York. udayan.guha@nih.gov.
Udayan
U
Guha
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D040901:Proteomics; D015398:Signal Transduction / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D047428:Protein Kinase Inhibitors; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases