Open AccessKrüppel‐like factor 4 promotes c‐Met amplification‐mediated gefitinib resistance in non‐small‐cell lung cancer
Author(s) -
Feng Wei,
Xie Qianyi,
Liu Suo,
Ji Ying,
Li Chunyun,
Wang Chunle,
Jin Longyu
Publication year - 2018
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.13601
Subject(s) - gefitinib , cancer research , epidermal growth factor receptor , gene knockdown , lung cancer , protein kinase b , medicine , apoptosis , cancer , oncology , chemistry , biochemistry
Gefitinib has been widely used in the first‐line treatment of advanced EGFR ‐mutated non‐small‐cell lung cancer ( NSCLC ). However, many NSCLC patients will acquire resistance to gefitinib after 9‐14 months of treatment. This study revealed that Krüppel‐like factor 4 ( KLF 4 ) contributes to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells. We observed that KLF 4 was overexpressed in c‐Met‐overexpressing NSCLC cells and tissues. Knockdown of KLF 4 increased tumorigenic properties in gefitinib‐resistant NSCLC cell lines without c‐Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib‐resistant NSCLC cells with c‐Met overexpression, whereas overexpression of KLF 4 reduced gefitinib sensitivity in gefitinib‐sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF 4 contributed to the formation of gefitinib resistance in c‐Met‐overexpressing NSCLC cells by inhibiting the expression of apoptosis‐related proteins under gefitinib treatment and activating the c‐Met/Akt signaling pathway by decreasing the inhibition of β‐catenin on phosphorylation of c‐Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF 4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c‐Met overexpression.