Research Article: Reverse epithelial-mesenchymal transition contributes to the regain of drug sensitivity in tyrosine kinase inhibitor-resistant non-small cell lung cancer cells

Date Published: July 6, 2017

Publisher: Public Library of Science

Author(s): An-Fu Lee, Man-Chin Chen, Chao-Ju Chen, Chih-Jen Yang, Ming-Shyang Huang, Yu-Peng Liu, Aamir Ahmad.


Tyrosine kinase inhibitors (TKIs) are currently the first-line treatment for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. These patients receive platinum-based chemotherapy as the second-line treatment after they develop resistance to TKIs. Many patients regain sensitivity to the TKIs used in the first-line treatment after the failure of chemotherapy. However, the molecular mechanism for the regain of TKI sensitivity is largely unknown. In this study, we established gefitinib-resistant PC9 and HCC827 cell lines, which did not harbor the EGFR T790M mutation and MET amplification but exhibited the epithelial-mesenchymal transition (EMT) phenotype. Overexpression of EMT inducers, Snail or Slug, in the parental lines promoted their resistance to gefitinib. The gefitinib-resistant cell lines regained their sensitivity to gefitinib and displayed reverse EMT phenotypes after long-term culture in gefitinib-free culture medium. Blockage of reverse EMT by stable expression of Snail or Slug prevented the regain of TKI sensitivity. In conclusion, reverse EMT is one of the major mechanisms for the regain of TKI sensitivity in TKI-resistant NSCLC cells, suggesting that the development of small molecules targeting the EMT process may prolong the efficacy of TKIs in NSCLC patients with EGFR mutations.

Partial Text

Approximately 50% of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations, such as exon 19 deletion and L858R point mutation, receive tyrosine-kinase inhibitors (TKIs) as their first-line treatment. Despite the initial response to TKI therapy, the tumor eventually recurs due to acquired drug resistance to the TKIs. In 50% of these patients, the resistance against TKIs can be explained by secondary EGFR mutations, mainly T790M point mutation. A third-generation TKI, osimertinib, targeting the EGFR T790M mutation has been recently developed and prolongs disease-free survival of NSCLC patients [1].

Since the discovery of TKIs, targeted therapy has become the most effective way to manage lung cancer. Despite the initial response of patients to TKIs, most of the patients still experience tumor recurrence due to acquired resistance to TKI and receive chemotherapy as their second-line treatment [26]. However, clinical and pre-clinical studies have revealed that TKI resistance is a transient event and may be reversed by the long-term culture of TKI-resistant lung cancer cells in TKI-free medium or by treatment with inhibitors of insulin-like growth factor 1 receptor or chromatin-modifying agents [7]. In the current study, we demonstrated that EMT is one of the major causes of gefitinib resistance in two NSCLC cell lines. In addition, the regain of TKI sensitivity could be mediated by reversal of EMT, since the blockage of reverse EMT by the constitutive expression of EMT inducers, Snail and Slug, can inhibit this effect. Our findings provide an important insight showing that EMT inhibitors may sensitize lung cancer cells to TKIs and prolong the efficacy of TKIs in lung cancer patients who carry EGFR mutations.




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