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EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells
| Content Provider | Semantic Scholar |
|---|---|
| Author | Chang, Hyun Sung, Ji Hea Moon, Sung Ung Kim, Han-Soo Kim, Jin Won Lee, Jong Seok |
| Copyright Year | 2017 |
| 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. |
| Starting Page | 9 |
| Ending Page | 18 |
| Page Count | 10 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://synapse.koreamed.org/Synapse/Data/PDFData/0069YMJ/ymj-58-9.pdf |
| PubMed reference number | 27873490 |
| Alternate Webpage(s) | https://doi.org/10.3349/ymj.2017.58.1.9 |
| DOI | 10.3349/ymj.2017.58.1.9 |
| Journal | Yonsei medical journal |
| Volume Number | 58 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Adenocarcinoma of lung (disorder) Carcinoma of lung E7080 Growth Factor Receptors Hepatocyte Malignant neoplasm of lung Mutation Non-Small Cell Lung Carcinoma Oncogene, RET Oncogenes Patients Protein Tyrosine Kinase Proto-Oncogenes RET gene RNA RNA, Small Interfering Tyrosine Kinase Inhibitors [MoA] Vandetanib benefit bypass cancer cell cetuximab gefitinib sorafenib sunitinib |
| Content Type | Text |
| Resource Type | Article |
