title: Volitinib, a potent and highly selective c-Met inhibitor, effectively blocks c-Met signaling and growth in c-MET amplified gastric cancer patient-derived tumor xenograft models.
abstract: OBJECTIVE
  To investigate the incidence of cMET gene copy number changes and protein overexpression in Chinese gastric cancer (GC) and to preclinically test the hypothesis that the novel, potent and selective cMET small-molecule inhibitor volitinib, will deliver potent anti-tumor activity in cMET-dysregulated GC patient-derived tumor xenograft (PDX) models.
  
  
  METHODS
  A range of assays were used and included; in vitro cell line panel screening and pharmacodynamic (PD) analysis, cMET fluorescence in-situ hybridization (FISH) and immunohistochemical (IHC) tissue microarray (TMA) analysis of Chinese GC (n = 170), and anti-tumor efficacy testing and PD analysis of gastric PDX models using volitinib.
  
  
  RESULTS
  The incidence of cMET gene amplification and protein overexpression within Chinese patient GC tumors was 6% and 13%, respectively. Volitinib displayed a highly selective profile across a gastric cell line panel, potently inhibiting cell growth only in those lines with dysregulated cMET (EC50 values 0.6 nM/L-12.5 nM/L). Volitinib treatment led to pharmacodynamic modulation of cMET signaling and potent tumor stasis in 3/3 cMET-dysregulated GC PDX models, but had negligible activity in a GC control model.
  
  
  CONCLUSIONS
  This study provides an assessment of tumor cMET gene copy number changes and protein overexpression incidence in a cohort of Chinese GC patients. To our knowledge, this is the first study to demonstrate anti-tumor efficacy in a panel of cMET-dysregulated gastric cancer PDX models, using a novel selective cMET-inhibitor (volitinib). Thus, the translational science presented here provides strong rationale for the investigation of volitinib as a therapeutic option for patients with GC tumors harboring amplified cMET.
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China. Electronic address: paul.gavine@astrazeneca.com.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gavine
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Ren
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Han
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lv
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Shiming
authors.initials: S
authors.lastname: Fan
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Xu
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Yuan Jie
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Tianwei
authors.initials: T
authors.lastname: Zhang
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Haihua
authors.initials: H
authors.lastname: Fu
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Yongjuan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Huiying
authors.initials: H
authors.lastname: Wang
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Shirlian
authors.initials: S
authors.lastname: Xu
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhou
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Xinying
authors.initials: X
authors.lastname: Su
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: XiaoLu
authors.initials: X
authors.lastname: Yin
authors.affiliation: AstraZeneca, Asia & Emerging Markets iMed, AstraZeneca Global R&D, 199 LiangJing Road, ZhangJiang Hi-Tech Park, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Linfang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Qing
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Longxian
authors.initials: L
authors.lastname: Jiao
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Su
authors.affiliation: Hutchison Medi Pharma Ltd, 720 Cai Lun Road, Zhangjiang Hi-Tech Park, Shanghai, China.
authors.forename: Q May
authors.initials: QM
authors.lastname: Wang
mesh_terms: D000818:Animals; D044466:Asian People; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D005784:Gene Amplification; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D011719:Pyrazines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D014227:Triazines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011719:Pyrazines; D014227:Triazines; C000593259:1-(1-(imidazo(1,2-a)pyridin-6-yl)ethyl)-6-(1-methyl-1H-pyrazol-4-yl)-1H-(1,2,3)triazolo(4,5-b)pyrazine; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Gastric cancer; PDX; Small molecule; Tyrosine kinase inhibitor; Volitinib; cMET