Epithelial to Mesenchymal Transition in an Epidermal Growth Factor Receptor-Mutant Lung Cancer Cell Line with Acquired Resistance to Erlotinib.
Suda, Kenichi MD *+; Tomizawa, Kenji MD *; Fujii, Makiko DDS ++; Murakami, Hideki MD ++; Osada, Hirotaka MD ++; Maehara, Yoshihiko MD +; Yatabe, Yasushi MD [S]; Sekido, Yoshitaka MD ++; Mitsudomi, Tetsuya MD *
Journal of Thoracic Oncology.
6(7):1152-1161, July 2011.
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Introduction: Mesenchymal status is related to "inherent resistance" to gefitinib or erlotinib in non-small cell lung cancer without epidermal growth factor receptor(EGFR) mutations. In addition, a recent report showed that the epithelial to mesenchymal transition (EMT) plays a role in acquired resistance to gefitinib in A549 cells, which harbor a KRAS mutation. However, recent clinical studies revealed that gefitinib or erlotinib are highly effective in the treatment of non-small cell lung cancer with EGFR mutations.
Methods: We developed resistant cells (HCC4006ER) from erlotinib-sensitive HCC4006 cells harboring an EGFR deletion mutation by chronic exposure to increasing concentrations of erlotinib. Acquired resistance mechanisms of HCC4006ER cells were analyzed.
Results: Neither known resistance mechanisms nor novel molecules that may confer erlotinib resistance were identified using candidate or comprehensive analyses. In addition, HCC4006ER cells lost dependency for EGFR. However, we found that HCC4006ER cells acquired a mesenchymal phenotype and exhibited down-regulation of E-cadherin expression (2.7 x 10-3 times compared with parental cells). We also found that the histone deacetylase inhibitor, MS-275, restored E-cadherin expression and moderate sensitivity to erlotinib in HCC4006ER cells, on the other hand, transforming growth factor beta, an inducer of EMT, led to moderate erlotinib resistance in HCC4006 parental cells.
Conclusions: This is the first report of a relationship between EMT and erlotinib acquired resistance in an erlotinib sensitive EGFR-mutant lung cancer cell line. Our results indicate that it would be important to consider the influence of EMT in the development of treatments against acquired resistance to gefitinib or erlotinib.
(C) 2011International Association for the Study of Lung Cancer