ABSTRACT
Nonsmall cell lung cancer (NSCLC) cells harboring mutations in the epidermal growth factor receptor (EGFR) gene initially respond well to EGFR tyrosine kinase inhibitors (TKI), including gefitinib. However the tumor cells will invariably develop acquired resistance to the drug. The EGFR T790M mutation is generally considered to be the molecular genetic basis of acquired TKI resistance. The present study aimed to explore how the T790M mutation induces tumor cells to escape inhibition by TKI treatment. An acquired gefitinibresistant cell line (NCIH1975/GR) was generated from the NCIH1975 human NSCLC cell line, which harbors the sensitive L858R and resistant T790M mutations of EGFR. The resistant cell line was established by exposing the cells intermittently to increasing concentrations of gefitinib. The mechanisms by which NSCLC acquires resistance to TKIs based on the T790M mutation, were investigated by detecting the protein expression levels of the EGFR/Kirsten rat sarcoma viral oncogene homolog (KRAS)/vRaf murine sarcoma viral oncogene homolog B (BRAF) transduction pathway, and epithelialmesenchymal transition (EMT) with immunocytochemistry. The resistance of the NCIH1975/GR cells to gefitinib was 2.009fold, as compared with the parent cells; however, the protein expression levels of EGFR, KRAS and BRAF were lower in the resistant cells. Some mesenchymal morphology was observed in the NCIH1975/GR cells, alongside a decreasing Ecadherin expression and increasing vimentin expression. These results suggest that the reactivation of the EGFR/KRAS/BRAF transduction pathway was not detected in the NCIH1975/GR cells. EMT may have an important role in the development of acquired resistance to EGFRTKIs in NSCLC cells with sensitivity and resistance mutations.