Yonsei Med J.  2017 Jan;58(1):9-18. 10.3349/ymj.2017.58.1.9.

EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells

• Chang H
• Sung JH
• Moon SU
• Kim HS
• Kim JW
• Lee JS

• KMID: 2374183
• DOI: http://doi.org/10.3349/ymj.2017.58.1.9

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.

Keyword

Lung cancer; RET oncogene; tyrosine kinase inhibitor; resistance; epidermal growth factor

MeSH Terms

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
Cetuximab
Epidermal Growth Factor
Hepatocyte Growth Factor
Indoles
Phenylurea Compounds
Piperidines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-ret
Pyrroles
Niacinamide
Quinazolines
RNA, Small Interfering
Receptor, Epidermal Growth Factor
fms-Like Tyrosine Kinase 3