Despite the effectiveness of
imatinib, most
gastrointestinal stromal tumors (GISTs) develop resistance to the treatment, mainly due to the reactivation of KIT
tyrosine kinase activity.
Sunitinib, which inhibits the phosphorylation of KIT and
vascular endothelial growth factor (
VEGF) receptor, has been established as second-line
therapy for GISTs. The recently-developed
heat shock protein 90 (HSP90) inhibitor pimitespib (PIM; TAS-116) demonstrated clinical benefits in some clinical trials; however, the effects were limited. The aim of our study was therefore to clarify the effectiveness and mechanism of the combination of PIM with
sunitinib for
imatinib-resistant GISTs. We evaluated the efficacy and mechanism of the combination of PIM with
sunitinib against
imatinib-resistant GIST using
imatinib-resistant GIST cell lines and murine xenograft models. In vitro analysis demonstrated that PIM and
sunitinib combination
therapy strongly inhibited growth and induced apoptosis in
imatinib-resistant GIST cell lines by inhibiting KIT signaling and decreasing auto-phosphorylated KIT in the Golgi apparatus. In addition, PIM and
sunitinib combination
therapy enhanced antitumor responses in the murine xenograft models compared to individual
therapies. Further analysis of the xenograft models showed that the combination
therapy not only downregulated the KIT signaling pathway but also decreased the
tumor microvessel density. Furthermore, we found that PIM suppressed
VEGF expression in GIST cells by suppressing
protein kinase D2 and
hypoxia-inducible factor-1 alpha, which are both HSP90 client
proteins. In conclusion, the combination of PIM and
sunitinib is effective against
imatinib-resistant GIST via the downregulation of KIT signaling and angiogenic signaling pathways.