Combination of pimitespib (<scp>TAS</scp>‐116) with sunitinib is an effective therapy for imatinib‐resistant gastrointestinal stromal tumors
Ryugo Teranishi, Tsuyoshi Takahashi, Yuuki Obata, Toshirou Nishida, Shuichi Ohkubo, Hiromi Kazuno, Yurina Saito, Satoshi Serada, Minoru Fujimoto, Yukinori Kurokawa, Takuro Saito, Kazuyoshi Yamamoto, Kotaro Yamashita, Koji Tanaka, Tomoki Makino, Kiyokazu Nakajima, Seiichi Hirota, Tetsuji Naka, Hidetoshi Eguchi, Yuichiro� Doki
Abstract
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.