title: MET Inhibition in Clear Cell Renal Cell Carcinoma.
abstract: 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.
authors.affiliation: 1. Department of Urology, Yale School of Medicine; 5. Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zuoquan
authors.initials: Z
authors.lastname: Xie
authors.affiliation: 2. Urologic Oncology Branch, National Cancer Institute.
authors.forename: Young H
authors.initials: YH
authors.lastname: Lee
authors.affiliation: 1. Department of Urology, Yale School of Medicine.
authors.forename: Marta
authors.initials: M
authors.lastname: Boeke
authors.affiliation: 3. Department of Medicine, Section of Medical Oncology, Yale School of Medicine.
authors.forename: Lucia B
authors.initials: LB
authors.lastname: Jilaveanu
authors.affiliation: 4. Department of Pathology, Yale School of Medicine, New Haven, USA.
authors.forename: Zongzhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: 2. Urologic Oncology Branch, National Cancer Institute.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Bottaro
authors.affiliation: 3. Department of Medicine, Section of Medical Oncology, Yale School of Medicine.
authors.forename: Harriet M
authors.initials: HM
authors.lastname: Kluger
authors.affiliation: 1. Department of Urology, Yale School of Medicine.
authors.forename: Brian
authors.initials: B
authors.lastname: Shuch
keywords: HGF; MET; VEGFR2; XL184; cabozantinib.; clear cell Carcinoma