Abstract
BackgroundThe resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer.MethodsWe compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples.ResultsOur results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma.ConclusionOur findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.
Highlights
The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-Tyrosine kinase inhibitor (TKI)) is one of the unconquered frontiers in chemotherapy
Mitogen-inducible gene 6 (Mig-6) expression is higher in Gefitinib-resistant PC9 cells than in parental PC9 cells We examined Mig-6 expression in PC9 cells harboring the EGFR exon 19 deletion and PC9/GR cells, which have EGFR-TKI resistance with an acquired T790M mutation
The mRNA level of EGFR was significantly higher in PC9/GR cells (Fig. 1d). These results suggest that Mig-6 may be involved in EGFR-TKI resistance and the regulation of EGFR expression
Summary
The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Lung cancer is still the main cause of cancer related deaths, but there have been significant improvements in the diagnosis and treatment of lung cancer over the last decade [1,2,3,4,5,6] Targeted therapeutic agents such as epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors, as well as immunotherapeutic drugs targeting programmed cell death protein 1 or programmed deathligand 1 (PD-L1), have changed the treatment of lung cancer and provided other treatment options for patients with advanced and refractory lung cancer [7, 8]. In order to identify crucial targets of EGFR-TKI resistance, one has to initially understand regulators of EGFR signaling
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