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EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells
Yonsei Medical Journal ; : 9-18, 2017.
Article in English | WPRIM | ID: wpr-222311
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.
Subject(s)

Full text: Available Index: WPRIM (Western Pacific) Main subject: Phenylurea Compounds / Piperidines / Pyrroles / Quinazolines / Gene Rearrangement / Adenocarcinoma / Signal Transduction / Hepatocyte Growth Factor / Niacinamide / Drug Resistance, Neoplasm Type of study: Prognostic study Limits: Humans Language: English Journal: Yonsei Medical Journal Year: 2017 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Phenylurea Compounds / Piperidines / Pyrroles / Quinazolines / Gene Rearrangement / Adenocarcinoma / Signal Transduction / Hepatocyte Growth Factor / Niacinamide / Drug Resistance, Neoplasm Type of study: Prognostic study Limits: Humans Language: English Journal: Yonsei Medical Journal Year: 2017 Type: Article