Molecular Cancer Therapeutics vol:10 issue:10 pages:1897-1908
The activity of the receptor tyrosine kinase KIT is crucial for gastrointestinal stromal tumor (GIST) growth and survival. Imatinib (IMA) and sunitinib ( SUN) 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 IMA or SUN 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 IMA (50 mg/kg twice daily), SUN (40 mg/kg once daily), IPI-504 (100 mg/kg 3 times per week), IPI-504+IMA or IPI-504+SUN. We evaluated tumor volume, proliferation and apoptosis, KIT expression and activation, as well as treatment adverse events. 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 IMA or SUN. On histology, liver damages were frequently observed in animals exposed to combination treatments. In conclusion, IPI-504 demonstrates consistent anti-tumor activity and induces KIT downregulation in GIST, as a single agent, and is more potent in combination with IMA or SUN. The sequence of drug administration in the combination arms warrants further studies.