title: The heat shock protein 90 inhibitor IPI-504 induces KIT degradation, tumor shrinkage, and cell proliferation arrest in xenograft models of gastrointestinal stromal tumors.
abstract: The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib and sunitinib are very effective in advanced GIST, but have no curative potential. The observation that heat shock protein 90 (HSP90) inhibition results in KIT degradation prompted us to assess the efficacy of the HSP90 inhibitor retaspimycin hydrochloride (IPI-504) alone or in combination with imatinib or sunitinib in two GIST xenografts with distinctive KIT mutations. Nude mice were grafted with human GIST carrying KIT exon 13 (GIST-882; n = 59) or exon 11 (GIST-PSW; n = 44) mutations and dosed with imatinib (50 mg/kg twice daily), sunitinib (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504 + imatinib, or IPI-504 + sunitinib. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as adverse events during treatment. Treatment with IPI-504 alone resulted in tumor regression, proliferation arrest, and induction of tumor necrosis. We documented downregulation of KIT and its signaling cascade in IPI-504-treated animals. Treatment effects were enhanced by combining IPI-504 with imatinib or sunitinib. On histologic examination, liver damage was frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 shows consistent antitumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with imatinib or sunitinib. The sequence of drug administration in the combination arms warrants further studies.
authors.affiliation: Laboratory of Experimental Oncology and Department of General Medical Oncology, University Hospital Gasthuisberg, Catholic University of Leuven, Herestraat 49, bus 815, 3000 Leuven, Belgium. giuseppe.floris@uzleuven.be
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Floris
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wozniak
authors.forename: Cristiana
authors.initials: C
authors.lastname: Stefan
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.forename: Gavino
authors.initials: G
authors.lastname: Faa
authors.forename: Kathleen
authors.initials: K
authors.lastname: Machiels
authors.forename: Ulla
authors.initials: U
authors.lastname: Vanleeuw
authors.forename: Raf
authors.initials: R
authors.lastname: Sciot
authors.forename: Patrick
authors.initials: P
authors.lastname: Schöffski
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001549:Benzamides; D016227:Benzoquinones / Q000008:administration & dosage / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000008:administration & dosage; D047029:Lactams, Macrocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D010879:Piperazines / Q000008:administration & dosage; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D000077210:Sunitinib; D023041:Xenograft Model Antitumor Assays
chemical_list: D001549:Benzamides; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D047029:Lactams, Macrocyclic; D010879:Piperazines; D011743:Pyrimidines; D011758:Pyrroles; C112765:tanespimycin; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D000077210:Sunitinib