Teranishi Ryugo, Takahashi Tsuyoshi, Obata Yuuki, Nishida Toshirou, Ohkubo Shuichi, Kazuno Hiromi, Saito Yurina, Serada Satoshi, Fujimoto Minoru, Kurokawa Yukinori, Saito Takuro, Yamamoto Kazuyoshi, Yamashita Kotaro, Tanaka Koji, Makino Tomoki, Nakajima Kiyokazu, Hirota Seiichi, Naka Tetsuji, Eguchi Hidetoshi, Doki Yuichiro
Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita-City, Osaka, Japan.
National Cancer Center Research Institute, Laboratory of Intracellular Traffic and Oncology, Tsukiji, Japan.
Int J Cancer. 2023 Jun 15;152(12):2580-2593. doi: 10.1002/ijc.34461. Epub 2023 Feb 21.
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.
尽管伊马替尼有效，但大多数胃肠道间质瘤（GIST）会对该治疗产生耐药性，主要原因是KIT酪氨酸激酶活性的重新激活。舒尼替尼可抑制KIT和血管内皮生长因子（VEGF）受体的磷酸化，已被确立为GIST的二线治疗药物。最近开发的热休克蛋白90（HSP90）抑制剂匹美替尼（PIM；TAS-116）在一些临床试验中显示出临床益处；然而，效果有限。因此，我们研究的目的是阐明PIM与舒尼替尼联合用于伊马替尼耐药GIST的有效性和机制。我们使用伊马替尼耐药GIST细胞系和小鼠异种移植模型评估了PIM与舒尼替尼联合治疗伊马替尼耐药GIST的疗效和机制。体外分析表明，PIM与舒尼替尼联合治疗通过抑制KIT信号传导和降低高尔基体中自磷酸化KIT，强烈抑制伊马替尼耐药GIST细胞系的生长并诱导其凋亡。此外，与单独治疗相比，PIM与舒尼替尼联合治疗增强了小鼠异种移植模型中的抗肿瘤反应。对异种移植模型的进一步分析表明，联合治疗不仅下调了KIT信号通路，还降低了肿瘤微血管密度。此外，我们发现PIM通过抑制蛋白激酶D2和缺氧诱导因子-1α（二者均为HSP90客户蛋白）来抑制GIST细胞中的VEGF表达。总之，PIM与舒尼替尼联合通过下调KIT信号传导和血管生成信号通路对伊马替尼耐药GIST有效。
