MET Inhibition in Clear Cell Renal Cell Carcinoma

被引:22
作者
Xie, Zuoquan [1 ,5 ]
Lee, Young H. [2 ]
Boeke, Marta [1 ]
Jilaveanu, Lucia B. [3 ]
Liu, Zongzhi [4 ]
Bottaro, Donald P. [2 ]
Kluger, Harriet M. [3 ]
Shuch, Brian [1 ]
机构
[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
来源
JOURNAL OF CANCER | 2016年 / 7卷 / 10期
基金
美国国家卫生研究院;
关键词
HGF; MET; clear cell Carcinoma; VEGFR2; XL184; cabozantinib; TYROSINE KINASE; TUMOR-CELLS; C-MET; GROWTH; PROTOONCOGENE; HEPATOCYTE; MUTATIONS; PATHWAY; PROTEIN; ACTS;
D O I
10.7150/jca.14604
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
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.
引用
收藏
页码:1205 / 1214
页数:10
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