The TGFβ-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors

Evgeny Izumchenko, Xiaofei Chang, Christina Michailidi, Luciane Tsukamoto Kagohara, Rajani Ravi, Keren Paz, Mariana Brait Rodrigues De Oliveira, Mohammad Hoque, Shizhang Ling, Atul Bedi, David Sidransky

Research output: Contribution to journalArticle

Abstract

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 withEMTand 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.

Original languageEnglish (US)
Pages (from-to)3995-4005
Number of pages11
JournalCancer Research
Volume74
Issue number14
DOIs
StatePublished - Jul 15 2014

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Epithelial-Mesenchymal Transition
Transforming Growth Factors
MicroRNAs
Mitogens
Epidermal Growth Factor Receptor
Phosphotransferases
Genes
Neoplasms
Protein-Tyrosine Kinases
Biomarkers
Molecular Targeted Therapy
Gene Regulatory Networks
Tumor Biomarkers
Pancreatic Neoplasms
Heterografts
Lung Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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The TGFβ-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. / Izumchenko, Evgeny; Chang, Xiaofei; Michailidi, Christina; Tsukamoto Kagohara, Luciane; Ravi, Rajani; Paz, Keren; Brait Rodrigues De Oliveira, Mariana; Hoque, Mohammad; Ling, Shizhang; Bedi, Atul; Sidransky, David.

In: Cancer Research, Vol. 74, No. 14, 15.07.2014, p. 3995-4005.

Research output: Contribution to journalArticle

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AU - Brait Rodrigues De Oliveira, Mariana

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