The novel heat shock protein 90 inhibitor, IPI-493, is highly effective in human gastrostrointestinal stromal tumor (GIST) xenografts carrying heterogeneous KIT mutations
Menée à l'aide de xénogreffes de tumeurs stromales gastrointestinales porteuses de mutations KIT, cette étude évalue l'activité d'un nouvel inhibiteur de la protéine de choc thermique 90, seul ou en combinaison avec de l'imatinib ou du sunitinib
Purpose: 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 heat shock protein 90 (HSP90) inhibitor IPI-493 alone, or in combination with IMA or SUN in GIST xenografts with KIT mutations. Experimental Design: 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: 1) control, sterile water; 2) IMA alone; 3) SUN alone; 4) IPI-493 alone; 5) IPI-493+IMA; and 6) IPI-493+SUN. Results: Treatment with IPI-493 resulted in tumor growth stabilization, variable proliferation arrest, induction of apoptosis and necrosis, and down-regulation 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. Conclusions: When administered as a single agent in a xenograft model, the HSP90 inhibitor IPI-493 has consistent anti-tumor activity and induces KIT down-regulation 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 anti-tumor response of IPI-493 is particularly enhanced in combination with SUN.