RRC ID 52358
Author Adachi Y, Watanabe K, Kita K, Kitai H, Kotani H, Sato Y, Inase N, Yano S, Ebi H.
Title Resistance mediated by alternative receptor tyrosine kinases in FGFR1-amplified lung cancer.
Journal 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.
Volume 38(11)
Pages 1063-1072
Published 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 5.072
Resource
Human and Animal Cells MRC-5(RCB0211)