Activation of the FGF2-FGFR1 Autocrine Pathway: A Novel Mechanism of Acquired Resistance to Gefitinib in NSCLC

被引：178

作者：

Terai, Hideki ^{[1
]}

Soejima, Kenzo ^{[1
]}

Yasuda, Hiroyuki ^{[1
]}

Nakayama, Sohei ^{[1
]}

Hamamoto, Junko ^{[1
]}

Arai, Daisuke ^{[1
]}

Ishioka, Kota ^{[1
]}

Ohgino, Keiko ^{[1
]}

Ikemura, Shinnosuke ^{[1
]}

Sato, Takashi ^{[1
]}

Yoda, Satoshi ^{[1
]}

Satomi, Ryosuke ^{[1
]}

Naoki, Katsuhiko ^{[2
]}

Betsuyaku, Tomoko ^{[1
]}

机构：

[1] Keio Univ, Sch Med, Dept Pulm Med, Tokyo 1608582, Japan

[2] Keio Univ, Sch Med, Keio Canc Ctr, Tokyo 1608582, Japan

来源：

MOLECULAR CANCER RESEARCH | 2013年 / 11卷 / 07期

关键词：

CELL LUNG-CANCER; FIBROBLAST-GROWTH-FACTOR; MUTATIONS; PROLIFERATION; INHIBITOR; RECEPTORS; ERLOTINIB; LINES;

D O I：

10.1158/1541-7786.MCR-12-0652

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Patients with non-small cell lung cancer (NSCLC) that harbors epidermal growth factor receptor (EGFR) mutations initially respond to EGFR-tyrosine kinase inhibitors (TKI) but eventually experience relapse. Acquired resistance to EGFR-TKIs is strongly associated with patient mortality. Thus, elucidation of the mechanism of acquired resistance to EGFR-TKIs is of great importance. In this study, gefitinib-resistant cell line models were established by long-term exposure to gefitinib using the gefitinib-sensitive lung cancer cell lines, PC9 and HCC827. Expression analyses indicated that both FGFR1 and FGF2 were increased in PC9 gefitinib-resistant (PC9 GR) cells as compared with PC9 naive (PC9 na) cells. Importantly, proliferation of gefitinib-resistant cells was dependent on the FGF2 -FGFR1 pathway. Mechanistically, inhibition of either FGF2 or FGFR1 by siRNA or FGFR inhibitor (PD173074) restored gefitinib sensitivity in PC9 GR cells. These data suggest that FGF2 (-)FGFR1 activation through an autocrine loop is a novel mechanism of acquired resistance to EGFR-TKIs.

引用

页码：759 / 767

页数：9

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