title: Effects of PKC412, nilotinib, and imatinib against GIST-associated PDGFRA mutants with differential imatinib sensitivity.
abstract: OBJECTIVE
  Activating mutations in platelet-derived growth factor receptor alpha (PDGFRA) have been reported in a subset of gastrointestinal stromal tumor (GIST) patients who do not express the mutant stem cell factor receptor c-kit. The responsiveness of mutant PDGFRA-positive GIST to imatinib depends on the location of the PDGFRA mutation; for example, the V561D juxtamembrane domain mutation is more sensitive to imatinib than the D842V kinase domain mutation. In this study, we compare the effects of 3 tyrosine kinase inhibitors, PKC412 and nilotinib, and imatinib, on 2 GIST-related PDGFRA mutants, V561D and D842V, which possess differential sensitivity to imatinib.
  
  
  METHODS
  The effects of PKC412, nilotinib, and imatinib, alone and in combination, were evaluated via in vitro proliferation studies performed with V561D- or D842V-PDGFRA mutants. The effects of nilotinib and PKC412, alone and combined, were investigated in vivo.
  
  
  RESULTS
  PKC412 potently inhibited the V561D-PDGFRA mutant in vitro and the D842V-PDGFRA mutant in vitro and in vivo. Both imatinib and nilotinib displayed potent activity in vitro against the V561D-PDGFRA mutant but were significantly less efficacious against D842V-PDGFRA. However, when combined with either imatinib or PKC412, nilotinib showed no evidence for antagonism and acted in a cooperative fashion against D842V-PDGFRA.
  
  
  CONCLUSIONS
  Our findings support the clinical testing of PKC412 for treatment of mutant PDGFRA-GIST. The data also support the use of nilotinib as a treatment option for V561D-PDGFRA-associated GIST, although the reduced sensitivity of D842V-PDGFRA probably limits the potential of nilotinib monotherapy for D842V-PDGFRA-associated GIST.
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA. Ellen_weisberg@dfci.harvard.edu
authors.forename: Ellen
authors.initials: E
authors.lastname: Weisberg
authors.forename: Renee D
authors.initials: RD
authors.lastname: Wright
authors.forename: Jingrui
authors.initials: J
authors.lastname: Jiang
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.forename: Daisy
authors.initials: D
authors.lastname: Moreno
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Doriano
authors.initials: D
authors.lastname: Fabbro
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hall-Meyers
authors.forename: Laurie
authors.initials: L
authors.lastname: Catley
authors.forename: Klaus
authors.initials: K
authors.lastname: Podar
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Kung
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001549:Benzamides; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000068877:Imatinib Mesylate; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D017354:Point Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D014443:Tyrosine; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha; C498826:nilotinib; D019311:Staurosporine; C059539:midostaurin