RRC ID 51943
著者 Chang H, Sung JH, Moon SU, Kim HS, Kim JW, Lee JS.
タイトル EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells.
ジャーナル Yonsei Med J
Abstract PURPOSE:Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes.
MATERIALS AND METHODS:The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined.
RESULTS:CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors.
CONCLUSION:EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.
巻・号 58(1)
ページ 9-18
公開日 2017-1-1
DOI 10.3349/ymj.2017.58.1.9
PII 58.9
PMID 27873490
PMC PMC5122657
MeSH Adenocarcinoma / drug therapy Adenocarcinoma / genetics* Cell Line, Tumor Cetuximab / pharmacology Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics* Epidermal Growth Factor / metabolism Epidermal Growth Factor / pharmacology* ErbB Receptors / genetics ErbB Receptors / metabolism Gefitinib Gene Rearrangement* Hepatocyte Growth Factor / pharmacology* Humans Indoles / pharmacology Lung Neoplasms / drug therapy Lung Neoplasms / genetics* MAP Kinase Signaling System Mutation* Niacinamide / analogs & derivatives Niacinamide / pharmacology Phenylurea Compounds / pharmacology Piperidines / pharmacology Protein Kinase Inhibitors / therapeutic use Proto-Oncogene Mas Proto-Oncogene Proteins c-ret / antagonists & inhibitors* Proto-Oncogene Proteins c-ret / genetics Pyrroles / pharmacology Quinazolines / pharmacology RNA, Small Interfering / pharmacology Signal Transduction / drug effects Sorafenib Sunitinib fms-Like Tyrosine Kinase 3 / metabolism
IF 1.914
引用数 16
リソース情報
ヒト・動物細胞 LC-2/ad(RCB0440)