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Epidermal growth factor receptor‐tyrosine kinase inhibitors ( EGFR ‐ TK I) 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 ( PPAR γ) 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  CT 10 oncogene homolog‐like  (  CRKL  ) amplification‐induced phosphatidylinositol 3‐kinase ( PI 3K)/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 ‐ TK I‐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.

cancer science

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