MET Inhibition in Clear Cell Renal Cell Carcinoma
文献类型：期刊论文
| 作者 | Xie, Zuoquan1,5 ; Lee, Young H.2; Boeke, Marta1; Jilaveanu, Lucia B.3; Liu, Zongzhi4; Bottaro, Donald P.2; Kluger, Harriet M.3; Shuch, Brian1
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| 刊名 | JOURNAL OF CANCER
 |
| 出版日期 | 2016 |
| 卷号 | 7期号:10页码:1205-1214 |
| ISSN号 | 1837-9664 |
| 关键词 | HGF MET clear cell Carcinoma VEGFR2 XL184 cabozantinib |
| DOI | 10.7150/jca.14604 |
| 文献子类 | Article |
| 英文摘要 | Background: Clear cell renal cell carcinoma (ccRCC) is the most lethal form of kidney cancer. Small molecule VEGFR inhibitors are widely used but are not curative and various resistance mechanisms such as activation of the MET pathway have been described. Dual MET/VEGFR2 inhibitors have recently shown clinical benefit but limited preclinical data evaluates their effects in ccRCC. Methods: An interrogation of the Cancer Genome Atlas (TCGA) dataset was performed to evaluate oncogenic alterations in the MET/VEGFR2 pathway. We evaluated the in vitro effects of Cabozantinib, a dual MET/VEGFR2 inhibitor, using a panel of ccRCC cell lines. Drug effects of cell viability and proliferation, migration, cell scatter, anchorage independent growth, and downstream MET/VEGFR2 signaling pathways were assessed. Results: Twelve percent of TCGA cases had possible MET/HGF oncogenic alterations with co-occurrence noted (p<0.001). MET/HGF altered cases had worse overall survival (p=0.044). Cabozantinib was a potent inhibitor of MET and VEGFR2 in vitro in our cell line panel. PI3K, MAPK and mTOR pathways were also suppressed by cabozantinib, however the effects on cell viability in vitro were modest. At nanomolar concentrations of cabozantinib, HGF-stimulated migration, invasion, cellular scattering and soft agar colony formation were inhibited. Conclusions: We provide further preclinical rationale for dual MET/VEGFR2 inhibition in ccRCC. While the MET pathway is implicated in VEGFR resistance, dual inhibitors may have direct anti-tumor effects in a patient subset with evidence of MET pathway involvement. Cabozantinib is a potent dual MET/VEGFR2 inhibitor, significantly inhibits cell migration and invasion in vitro and likely has anti-angiogenic effects similar to other VEGFR tyrosine kinase inhibitors. Future work involving in vivo models will be useful to better define mechanisms of potential anti-tumor activity. |
| WOS关键词 | ENDOTHELIAL-CELLS ; TYROSINE KINASE ; TUMOR-CELLS ; C-MET ; GROWTH ; PROTOONCOGENE ; METASTASIS ; HEPATOCYTE ; MUTATIONS ; PATHWAY |
| 资助项目 | CTSA Grant from the National Center for Advancing Translational Science (NCATS), a component of the National Institutes of Health (NIH)[KL2 TR000140] ; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research[00000000] ; China Scholarship Council[201404910330] |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| 出版者 | IVYSPRING INT PUBL |
| WOS记录号 | WOS:000378916200004 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276220]  |
| 专题 | 药理学第一研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Shuch, Brian |
| 作者单位 | 1.Yale Sch Med, Dept Urol, POB 208058, New Haven, CT 06520 USA; 2.NCI, Urol Oncol Branch, Bethesda, MD 20892 USA; 3.Yale Sch Med, Dept Med, Sect Med Oncol, New Haven, CT 06520 USA; 4.Yale Sch Med, Dept Pathol, New Haven, CT 06520 USA; 5.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Zuoquan,Lee, Young H.,Boeke, Marta,et al. MET Inhibition in Clear Cell Renal Cell Carcinoma[J]. JOURNAL OF CANCER,2016,7(10):1205-1214. |
| APA | Xie, Zuoquan.,Lee, Young H..,Boeke, Marta.,Jilaveanu, Lucia B..,Liu, Zongzhi.,...&Shuch, Brian.(2016).MET Inhibition in Clear Cell Renal Cell Carcinoma.JOURNAL OF CANCER,7(10),1205-1214. |
| MLA | Xie, Zuoquan,et al."MET Inhibition in Clear Cell Renal Cell Carcinoma".JOURNAL OF CANCER 7.10(2016):1205-1214. |
入库方式： OAI收割
来源：上海药物研究所
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