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.
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.
Drug Discovery and Development Division, Shizuoka Cancer Center Research Institute, Shizuoka, Japan.
Masakuni
M
Serizawa
Haruyasu
H
Murakami
Masaru
M
Watanabe
Toshiaki
T
Takahashi
Nobuyuki
N
Yamamoto
Yasuhiro
Y
Koh
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D047495:PPAR gamma / Q000819:agonists / Q000037:antagonists & inhibitors*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051899:Smad2 Protein / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors*; D014945:Wound Healing / Q000187:drug effects
D000970:Antineoplastic Agents; D047495:PPAR gamma; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D045162:Thiazolidinediones; D053781:Transforming Growth Factor beta2; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; C510342:efatutazone
Efatutazone; epidermal growth factor receptor-tyrosine kinase inhibitor resistance; motility; non-small cell lung cancer; peroxisome proliferator-activated receptor gamma