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

Cancer Science

Masakuni Serizawa²  Haruyasu Murakami¹  Masaru Watanabe²  Toshiaki Takahashi¹  Nobuyuki Yamamoto¹ 

[1] Division of Thoracic Oncology, Shizuoka Cancer Center, Shizuoka, Japan;Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan

关键词: Efatutazone;    epidermal growth factor receptor‐tyrosine kinase inhibitor resistance;    motility;    non‐small cell lung cancer;    peroxisome proliferator‐activated receptor gamma;   

DOI  :  10.1111/cas.12411

来源: Wiley

【 摘 要 】

Abstract

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) are effective for non-small cell lung cancers (NSCLC) with EGFR-activating mutations. However, most responders develop resistance. Efatutazone, a novel peroxisome proliferator-activated receptor gamma (PPARγ) agonist, is currently under clinical evaluation; it has antiproliferative effects and induces cellular morphological changes and differentiation. The present study investigated the effects of efatutazone in EGFR-TKI-resistant NSCLC cells, while focusing on cell motility. The PC-9-derived NSCLC cell lines PC-9ER and PC-9ZD, resistant to EGFR-TKI due to v-crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) amplification-induced phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homolog (AKT) activation and an EGFR T790M mutation, respectively, were used. These cells exhibit enhanced cell motility due to transforming growth factor β (TGF-β)/Smad2 family member 2 (Smad2) pathway activation. 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. Efatutazone suppressed increased TGF-β2 secretion from both cell lines (shown by ELISA) and downregulation of TGF-β2 transcription (observed by quantitative RT-PCR). Immunoblot analysis and luciferase assays revealed that efatutazone suppressed Smad2 phosphorylation and its transcriptional activity. 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.

【 授权许可】

CC BY-NC-ND   
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

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