The TGFβ-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors.
Although specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKI), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial-mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified. Here, we show that during transforming growth factor β (TGFβ)-mediated EMT, inhibition of the microRNAs 200 (miR200) family results in upregulated expression of the mitogen-inducible gene 6 (MIG6), a negative regulator of EGFR. The MIG6-mediated reduction of EGFR occurs concomitantly with a TGFβ-induced EMT-associated kinase switch of tumor cells to an AKT-activated EGFR-independent state. In a panel of 25 cancer cell lines of different tissue origins, we find that the ratio of the expression levels of MIG6 and miR200c is highly correlated with EMT and resistance to erlotinib. Analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild-type EGFR showed that the tumor MIG6(mRNA)/miR200 ratio was inversely correlated with response to erlotinib in vivo. Our data demonstrate that the TGFβ-miR200-MIG6 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors, and identify a low ratio of MIG6 to miR200 as a promising predictive biomarker of the response of tumors to EGFR TKIs.
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Evgeny
E
Izumchenko
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Xiaofei
X
Chang
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Christina
C
Michailidi
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Luciane
L
Kagohara
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Rajani
R
Ravi
Champions Oncology, Inc., Baltimore, Maryland.
Keren
K
Paz
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Mariana
M
Brait
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Mohammad O
MO
Hoque
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Shizhang
S
Ling
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and.
Atul
A
Bedi
Authors' Affiliations: Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine; and dsidrans@jhmi.edu.
David
D
Sidransky
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004789:Enzyme Activation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D009928:Organ Specificity / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C484017:ERRFI1 protein, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt