Peroxisome proliferator-activated receptor γ agonist efatutazone impairs transforming growth factor β2-induced motility of epidermal growth factor receptor tyrosine kinase inhibitor-resistant lung cancer cells.
Bottom Line: Efatutazone had no growth-inhibitory effect on the tested cells but inhibited the motility of EGFR-TKI-resistant cells in wound closure and transwell assays.Efatutazone plus erlotinib treatment provided greater inhibition of PC-9ER cell migration than efatutazone or erlotinib alone.These results suggest that efatutazone inhibits cell motility by antagonizing the TGF-β/Smad2 pathway and effectively prevents metastasis in NSCLC patients with acquired resistance to EGFR-TKI regardless of the resistance mechanism.
Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.Show MeSH
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Mentions: The EGFR-TKI-resistant cell lines, PC-9ER and PC-9ZD, were approximately 100-fold more resistant to erlotinib than PC-9 cells (Fig. S1). PC-9ER and PC-9ZD cells migrated faster to close a wound than the parental PC-9 cells (Fig. 1a), and this enhanced cell migration was also confirmed by a transwell assay (Fig. 1b). Erlotinib not only effectively abolished the motility of PC-9 cells but also attenuated the enhanced cell motility of PC-9ER cells (Fig. 1a,b). However, erlotinib could not suppress the enhanced cell motility of PC-9ZD cells harboring the T790M resistance mutation (Fig. 1a,b). These results suggest that continuous treatment with erlotinib may have a therapeutic effect by preventing metastasis even after EGFR-TKI failure, except in cases of resistance due to the T790M mutation. In contrast, efatutazone attenuated the motility of not only PC-9 and PC-9ER cells but also PC-9ZD cells in a dose-dependent manner (Fig. 1a and Fig. S2); this was also confirmed by the transwell assay (Fig. 1b). These results imply that efatutazone would be beneficial in preventing metastasis even after EGFR-TKI treatment failure, regardless of the resistance mechanism. Moreover, combined treatment with efatutazone and erlotinib showed a more potent inhibitory effect on the migration of PC-9ER cells than either treatment alone (Fig. 1b), indicating that this combination treatment may be effective for preventing metastasis in patients with EGFR-TKI-resistant NSCLC who do not harbor the EGFR T790M resistance mutation. Efatutazone had no significant antiproliferative effect on any of the tested cell lines (Fig. S1), indicating that cell motility and cell growth are driven by different mechanisms.
Affiliation: Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.