| RRC ID |
52358
|
| 著者 |
Adachi Y, Watanabe K, Kita K, Kitai H, Kotani H, Sato Y, Inase N, Yano S, Ebi H.
|
| タイトル |
Resistance mediated by alternative receptor tyrosine kinases in FGFR1-amplified lung cancer.
|
| ジャーナル |
Carcinogenesis
|
| Abstract |
Fibroblast growth factor receptor 1 (FGFR1) amplification has been identified in 10-20% of patients with squamous non-small-cell lung cancer. Preclinical models showed promising activity of specific FGFR inhibitors, but early clinical trials showed that only a small fraction of patients with FGFR1-amplified lung cancer responded to FGFR inhibitors. These unsatisfactory results were partly explained by heterogeneous amplicons around the 8p11 genomic region, leading to false-positive amplification results. Furthermore, discrepancies in the gene amplification and protein expression of FGFR1 were also reported. In this study, we identified the roles of alternative receptor tyrosine kinases (RTKs) in FGFR1-amplified lung cancer. These alternative RTKs dominantly activate phosphoinositide 3-kinase-AKT signaling and also mitigate sustained inhibition of mitogen-activated protein kinase signaling by FGFR inhibitors. The rebound activation of extracellular signal-regulated kinase phosphorylation was associated with sensitivity to the drugs. Combinatorial inhibition of alternative RTKs and FGFR1 was required to suppress both AKT and extracellular signal-regulated kinase phosphorylation and to induce key pro-apoptotic proteins BIM and p53 upregulated modulator of apoptosis (PUMA). Furthermore, even in FGFR inhibitor-sensitive NCI-H1581 lung cancer cells, MET-expressing clones were already detectable at a very low frequency before resistance induction. Selection of these pre-existing subclones resulted in FGFR inhibitor resistance because of the activation of AKT and extracellular signal-regulated kinase by MET signaling that was mediated by GRB2 associated binding protein 1 (GAB1). These results suggest that incomplete suppression of key survival signals led to intrinsic and acquired resistance to FGFR inhibitors. Our results may help explain the low clinical response rates to FGFR inhibitors in FGFR1-amplified lung cancer.
|
| 巻・号 |
38(11)
|
| ページ |
1063-1072
|
| 公開日 |
2017-10-26
|
| DOI |
10.1093/carcin/bgx091
|
| PII |
4100588
|
| PMID |
28968756
|
| MeSH |
Apoptosis / drug effects
Apoptosis / genetics
Carcinoma, Non-Small-Cell Lung / genetics
Carcinoma, Non-Small-Cell Lung / metabolism
Cell Line, Tumor
Extracellular Signal-Regulated MAP Kinases / genetics
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Amplification / drug effects
Gene Amplification / genetics*
HCT116 Cells
Humans
Lung Neoplasms / drug therapy
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism
Phosphatidylinositol 3-Kinases / genetics
Phosphatidylinositol 3-Kinases / metabolism
Phosphorylation / drug effects
Phosphorylation / genetics
Protein Kinase Inhibitors / pharmacology
Protein-Tyrosine Kinases / antagonists & inhibitors
Protein-Tyrosine Kinases / genetics*
Proto-Oncogene Proteins c-akt / genetics
Proto-Oncogene Proteins c-akt / metabolism
Receptor, Fibroblast Growth Factor, Type 1 / antagonists & inhibitors
Receptor, Fibroblast Growth Factor, Type 1 / genetics*
Signal Transduction / drug effects
Signal Transduction / genetics
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Up-Regulation / drug effects
Up-Regulation / genetics
|
| IF |
4.603
|
| 引用数 |
4
|
| リソース情報 |
| ヒト・動物細胞 |
MRC-5(RCB0211) |
