Abstract
KIT activity is crucial for gastrointestinal stromal tumors (GIST). Imatinib (IMA) and sunitinib (SUN) are very effective KIT-inhibitors in patients with advanced GIST but have no curative potential. We evaluated the efficacy of the novel HSP90 inhibitor IPI-493 alone, or in combination with IMA or SUN in GIST xenografts with KIT mutations. Nude mice (n = 98) were grafted bilaterally with human GIST carrying KIT exon 11 (GIST-PSW), KIT exon 9 (GIST-BOE), or double, KIT imatinib-sensitive exon 11 and imatinib-resistant exon 17 mutations (GIST-48). Mice were divided into six treatment groups and dosed orally for 15 days as follows: (i) control group, sterile water; (ii) IMA alone; (iii) SUN alone; (iv) IPI-493 alone; (v) IPI-493+IMA; and (vi) IPI-493+SUN. Treatment with IPI-493 resulted in tumor growth stabilization, variable proliferation arrest, induction of apoptosis and necrosis, and downregulation of KIT and its signaling cascade, especially in the GIST-BOE model. Significant reduction of vessel density was observed with IPI-493 treatment, and was equal to SUN treatment in GIST-PSW and GIST-BOE xenografts. IPI-493 treatment effects were enhanced in combination with TKIs, especially with IPI-493+SUN. In our hands, IPI-493 showed dose-dependent liver damages. When administered as a single agent in a xenograft model, the HSP90 inhibitor IPI-493 has consistent antitumor activity and induces KIT downregulation in GISTs with heterogeneous KIT mutations. IPI-493 synergizes with TKIs that are commonly used for the treatment of advanced or IMA-resistant GIST. The antitumor response of IPI-493 is particularly enhanced in combination with SUN.
Highlights
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancies of the digestive tractAuthors' Affiliations: 1Laboratory of Experimental Oncology and Department of General Medical Oncology, Departments of 2Pathology and 3Human Genetics, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium; 4Department of Pathology, University of Cagliari, Cagliari, Italy; and 5Infinity Pharmaceuticals, Inc., Cambridge, MassachusettsNote: Supplementary data for this article are available at Clinical Cancer Research Online.M
Significant reduction of vessel density was observed with IPI-493 treatment, and was equal to SUN treatment in gastrointestinal stromal tumors (GIST)-PSW and GIST-BOE xenografts
IPI-493 synergizes with tyrosine kinase inhibitors (TKI) that are commonly used for the treatment of advanced or IMAresistant GIST
Summary
Gastrointestinal stromal tumors (GIST) are the most common mesenchymal malignancies of the digestive tractAuthors' Affiliations: 1Laboratory of Experimental Oncology and Department of General Medical Oncology, Departments of 2Pathology and 3Human Genetics, University Hospital Gasthuisberg, Catholic University of Leuven, Leuven, Belgium; 4Department of Pathology, University of Cagliari, Cagliari, Italy; and 5Infinity Pharmaceuticals, Inc., Cambridge, MassachusettsNote: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).M. Debiec-Rychter and P. Scho€ffski contributed equally to this work.Current address for G. Floris: Department of Pathology, University Hospitals Leuven, Minderbroedersstraat 12, 3000 Leuven, Belgium.
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