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The TGF?-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that
induces resistance to EGFR inhibitors
#MMPMID24830724
Izumchenko E
; Chang X
; Michailidi C
; Kagohara L
; Ravi R
; Paz K
; Brait M
; Hoque MO
; Ling S
; Bedi A
; Sidransky D
Cancer Res
2014[Jul]; 74
(14
): 3995-4005
PMID24830724
show ga
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 ? (TGF?)-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 TGF?-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 TGF?-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.
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