Abstract
Abstract Background: CS-7017, a novel selective peroxisome proliferator-activated receptor gamma (PPARδ) agonist of thiazolidinedione class, has been reported to induce morphological change and cellular differentiation as well as its antiproliferative effects. A phase II clinical trial of CS-7017 in combination with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib is currently ongoing in advanced non-small cell lung cancer (NSCLC) patients. Though EGFR-TKIs are effective for NSCLCs with EGFR-activating mutations, the majority of responders eventually develop acquired resistance. We have previously reported that EGFR-TKI-resistant NSCLC cells acquire enhanced cell motility via activation of TGFβ pathway. In this study, we aim to investigate the effects of CS-7017 in EGFR-TKI-resistant NSCLC cells with a focus on cell motility. Materials and Methods: Erlotinib-resistant PC-9ER and gefitinib-resistant PC-9/ZD cells, established from PC-9 NSCLC cells with EGFR-activating mutation, were used for this study and constitutive PI3K/Akt activation and the EGFR T790M mutation have been previously shown to account for the acquired resistance, respectively. Growth-inhibitory effect of CS-7017 was evaluated by MTT assay. Wound closure assay and transwell assay were performed to evaluate the cell motility. The levels of TGFβ1 and 2 secretion were quantified by ELISA. Cellular mRNA levels of TGFB1 and TGFB2 were measured by qRT-PCR. Smad- or PPARδ-mediated transcriptional activity was analyzed by luciferase assay. Effects of CS-7017 on the molecules relevant to EGFR, TGFβ and PPARδ pathways were observed by immunoblot analysis. Results: Both PC-9ER and PC-9/ZD resistant cells showed the enhanced cell motility resulting from TGFβ2-induced activation of TGFβ pathway. CS-7017 showed significant inhibitory effect on the cell motility of the resistant cells but showed no growth-inhibitory effect. Moreover, combination treatment of CS-7017 and erlotinib resulted in better inhibition of the cell motility of PC-9ER cells. CS-7017 treatment was found to suppress the TGFβ2 secretion significantly resulting from downregulation of TGFB2 at transcriptional level and attenuated Smad2 phosphorylation was observed in the resistant cells. Smad-mediated transcriptional activity was also suppressed by CS-7017 treatment. CS-7017 treatment induced PPARδ-mediated transcriptional activity in PC-9 and PC-9/ZD cells but not in PC-9ER cells, suggesting that the inhibitory effect of CS-7017 on the cell motility of PC-9ER cells may not be due to direct activation of PPARδ signaling by CS-7017. Conclusions: These results imply that CS-7017 may serve as a potential therapeutic agent to prevent metastasis in NSCLC patients who develop acquired resistance to EGFR-TKIs regardless of the types of resistance mechanisms. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3802. doi:1538-7445.AM2012-3802
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