title: Activity of dasatinib, a dual SRC/ABL kinase inhibitor, and IPI-504, a heat shock protein 90 inhibitor, against gastrointestinal stromal tumor-associated PDGFRAD842V mutation.
abstract: OBJECTIVE
  Activating mutations in platelet-derived growth factor receptor-alpha (PDGFRA) have been reported in approximately 5% to 10% of patients with gastrointestinal stromal tumors (GIST). Imatinib efficiently inhibits the juxtamembrane PDGFRA mutations, whereas many tyrosine kinase domain activation loop PDGFRA mutations confer primary resistance to imatinib. In this study, we compared the efficacy of second-line tyrosine kinase inhibitors such as dasatinib, sorafenib, and nilotinib against two GIST-related PDGFRA mutants, PDGFRA(D842V) and PDGFRA(DeltaDIM842-844). In addition, we sought to investigate the inhibitory effect of the heat shock protein 90 inhibitor, IPI-504, on these mutants.
  
  
  METHODS
  Primary imatinib-resistant tumor cells and cell lines expressing imatinib-resistant PDGFRA(D842V) or imatinib-sensitive PDGFRA(DeltaDIM842-844) mutants were treated with different concentrations of dasatinib, sorafenib, nilotinib, and IPI-504. The effect of treatment on proliferation, survival, and signaling was determined.
  
  
  RESULTS
  All inhibitors tested exhibited a high efficacy toward the PDGFRA(DeltaDIM842-844) mutant. In contrast, ex vivo and in vitro assays revealed that only dasatinib potently inhibited the PDGFRA(D842V) isoform with an IC(50) value of 62 nmol/L. Sorafenib and nilotinib were significantly less efficacious against this mutation, inhibiting the PDGFRA kinase activity at >1,000 and >5,000 nmol/L, and suppressing the proliferation of the cells expressing the PDGFRA(D842V) mutant with an IC(50) value of 239 and 1,310 nmol/L, respectively. IPI-504 treatment potently inhibited PDGFRA kinase activity by inducing the degradation of PDGFRA(D842V) and PDGFRA(DeltaDIM842-844) at 256 and 182 nmol/L, respectively.
  
  
  CONCLUSIONS
  Treatment with dasatinib or the heat shock protein 90 inhibitor IPI-504 may provide a therapeutic alternative for GIST patients whose tumors carry the imatinib-resistant PDGFRA(D842V) mutant isoform.
authors.affiliation: Department of Human Genetics, K.U. Leuven, and VIB Department of Molecular and Developmental Genetics, VIB, Leuven, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: Dewaele
authors.forename: Bartosz
authors.initials: B
authors.lastname: Wasag
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Hans
authors.initials: H
authors.lastname: Prenen
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000069439:Dasatinib; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy*; D016313:Genes, abl; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D009154:Mutation / Q000187:drug effects; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000493:pharmacokinetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D013844:Thiazoles / Q000493:pharmacokinetics*; D014407:Tumor Cells, Cultured
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; C112765:tanespimycin; D020796:Receptor, Platelet-Derived Growth Factor alpha; D016315:Proto-Oncogene Proteins c-abl; D016392:Proto-Oncogene Proteins pp60(c-src); D000069439:Dasatinib