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.
journal_name
Yonsei Med Jjournal_title
Yonsei medical journalauthors
Chang H,Sung JH,Moon SU,Kim HS,Kim JW,Lee JSdoi
10.3349/ymj.2017.58.1.9subject
Has Abstractpub_date
2017-01-01 00:00:00pages
9-18issue
1eissn
0513-5796issn
1976-2437pii
58.9journal_volume
58pub_type
杂志文章abstract:PURPOSE:Most studies on immune tolerance of mesenchymal stem cells (MSCs) have been performed using MSCs derived from bone marrow, cord blood, or adipose tissue. MSCs also exist in the craniofacial area, specifically in teeth. The purpose of this study was to evaluate the mechanisms of immune tolerance of dental pulp-d...
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journal_title:Yonsei medical journal
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journal_title:Yonsei medical journal
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journal_title:Yonsei medical journal
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journal_title:Yonsei medical journal
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doi:10.3349/ymj.1990.31.4.375
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journal_title:Yonsei medical journal
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doi:10.3349/ymj.2006.47.5.667
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journal_title:Yonsei medical journal
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doi:10.3349/ymj.2005.46.5.700
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journal_title:Yonsei medical journal
pub_type: 杂志文章
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journal_title:Yonsei medical journal
pub_type: 杂志文章,评审
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pub_type: 杂志文章
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journal_title:Yonsei medical journal
pub_type: 杂志文章
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journal_title:Yonsei medical journal
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journal_title:Yonsei medical journal
pub_type: 杂志文章
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journal_title:Yonsei medical journal
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journal_title:Yonsei medical journal
pub_type: 杂志文章
doi:10.3349/ymj.2013.54.4.1020
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journal_title:Yonsei medical journal
pub_type: 杂志文章
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journal_title:Yonsei medical journal
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journal_title:Yonsei medical journal
pub_type: 杂志文章,评审
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pub_type: 临床试验,杂志文章
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journal_title:Yonsei medical journal
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更新日期:1990-09-01 00:00:00
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journal_title:Yonsei medical journal
pub_type: 杂志文章,评审
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更新日期:2003-06-30 00:00:00
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pub_type: 杂志文章
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更新日期:2013-03-01 00:00:00