Combined treatment with erlotinib and a transforming growth factor-β type I receptor inhibitor effectively suppresses the enhanced motility of erlotinib-resistant non-small-cell lung cancer cells.

INTRODUCTION

: Despite an initial dramatic response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, the majority of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations develop acquired resistance. Therefore, there is an urgent need to elucidate the unknown mechanisms and biological behaviors of EGFR TKI-resistant lung tumors. We investigated the motility of EGFR TKI-resistant cells, as these characteristics are relevant to cancer metastasis.

METHODS

: Erlotinib-resistant PC-9ER cells were generated from PC-9 NSCLC cells, which harbor an EGFR-activating mutation, and used in this study. We investigated the involvement of the transforming growth factor beta (TGF-β) pathway in cell motility, and tested the effects of erlotinib and TGF-β type I receptor (RI) inhibition on cell motility.

RESULTS

: PC-9ER cells displayed enhanced motility resulting from autocrine activation of the TGF-β pathway. Increased TGF-β2 secretion resulting from TGF-β2 up-regulation at the transcriptional level was suggested to be responsible for the phosphorylation of Smad2 and the subsequently elevated transcriptional regulatory activity in PC-9ER cells. The motility of PC-9ER cells was suppressed by treatment with either the TGF-βRI inhibitor LY364947 or erlotinib, and greater suppression was observed when used in combination. LY364947 or erlotinib exerted no growth-inhibitory effects, suggesting that motility and growth are driven by different signaling pathways in PC-9ER cells.

CONCLUSIONS

: Our results imply that blockade of the TGF-β signaling pathway combined with continuous EGFR TKI treatment will be beneficial in preventing metastasis in patients with EGFR TKI-resistant NSCLC without the EGFR T790M resistance mutation.