- Author:
Hyun CHANG
1
;
Ji Hea SUNG
;
Sung Ung MOON
;
Han Soo KIM
;
Jin Won KIM
;
Jong Seok LEE
Author Information
- Publication Type:Original Article
- Keywords: Lung cancer; RET oncogene; tyrosine kinase inhibitor; resistance; epidermal growth factor
- MeSH: Adenocarcinoma/drug therapy/*genetics; Cell Line, Tumor; Cetuximab/pharmacology; Drug Resistance, Neoplasm/drug effects/*genetics; Epidermal Growth Factor/metabolism/*pharmacology; *Gene Rearrangement; Hepatocyte Growth Factor/*pharmacology; Humans; Indoles/pharmacology; Lung Neoplasms/drug therapy/*genetics; MAP Kinase Signaling System; *Mutation; Niacinamide/analogs & derivatives/pharmacology; Phenylurea Compounds/pharmacology; Piperidines/pharmacology; Protein Kinase Inhibitors/therapeutic use; Proto-Oncogene Proteins c-ret/*antagonists & inhibitors/genetics; Pyrroles/pharmacology; Quinazolines/pharmacology; RNA, Small Interfering/pharmacology; Receptor, Epidermal Growth Factor/genetics/metabolism; Signal Transduction/drug effects; fms-Like Tyrosine Kinase 3/metabolism
- From:Yonsei Medical Journal 2017;58(1):9-18
- CountryRepublic of Korea
- Language:English
- 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.