title: The MET Inhibitor AZD6094 (Savolitinib, HMPL-504) Induces Regression in Papillary Renal Cell Carcinoma Patient-Derived Xenograft Models.
abstract: OBJECTIVE
  Papillary renal cell carcinoma (PRCC) is the second most common cancer of the kidney and carries a poor prognosis for patients with nonlocalized disease. The HGF receptor MET plays a central role in PRCC and aberrations, either through mutation, copy number gain, or trisomy of chromosome 7 occurring in the majority of cases. The development of effective therapies in PRCC has been hampered in part by a lack of available preclinical models. We determined the pharmacodynamic and antitumor response of the selective MET inhibitor AZD6094 in two PRCC patient-derived xenograft (PDX) models.
  
  
  METHODS
  Two PRCC PDX models were identified and MET mutation status and copy number determined. Pharmacodynamic and antitumor activity of AZD6094 was tested using a dose response up to 25 mg/kg daily, representing clinically achievable exposures, and compared with the activity of the RCC standard-of-care sunitinib (in RCC43b) or the multikinase inhibitor crizotinib (in RCC47).
  
  
  RESULTS
  AZD6094 treatment resulted in tumor regressions, whereas sunitinib or crizotinib resulted in unsustained growth inhibition. Pharmacodynamic analysis of tumors revealed that AZD6094 could robustly suppress pMET and the duration of target inhibition was dose related. AZD6094 inhibited multiple signaling nodes, including MAPK, PI3K, and EGFR. Finally, at doses that induced tumor regression, AZD6094 resulted in a dose- and time-dependent induction of cleaved PARP, a marker of cell death.
  
  
  CONCLUSIONS
  Data presented provide the first report testing therapeutics in preclinical in vivo models of PRCC and support the clinical development of AZD6094 in this indication.
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Alwin G
authors.initials: AG
authors.lastname: Schuller
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Barry
authors.affiliation: AstraZeneca, Cambridge, United Kingdom.
authors.forename: Rhys D O
authors.initials: RD
authors.lastname: Jones
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Henry
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Frigault
authors.affiliation: AstraZeneca, Alderley Park, United Kingdom.
authors.forename: Garry
authors.initials: G
authors.lastname: Beran
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: David
authors.initials: D
authors.lastname: Linsenmayer
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Maureen
authors.initials: M
authors.lastname: Hattersley
authors.affiliation: AstraZeneca, Cambridge, United Kingdom.
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.affiliation: AstraZeneca, Cambridge, United Kingdom.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wilson
authors.affiliation: Xentech, Evry, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.affiliation: Xentech, Evry, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Déas
authors.affiliation: Xentech, Evry, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Nicolle
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Ammar
authors.initials: A
authors.lastname: Adam
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Zinda
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Corinne
authors.initials: C
authors.lastname: Reimer
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Fawell
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts.
authors.forename: Edwin A
authors.initials: EA
authors.lastname: Clark
authors.affiliation: Oncology Innovative Medicines, AstraZeneca, Waltham, Massachusetts. Celina.Dcruz@astrazeneca.com.
authors.forename: Celina M
authors.initials: CM
authors.lastname: D'Cruz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D000077547:Crizotinib; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors* / Q000235:genetics; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077210:Sunitinib; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D011720:Pyrazoles; D011725:Pyridines; D011758:Pyrroles; 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; D000077547:Crizotinib; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000077210:Sunitinib