Wu Xiyu, Yamashita Kohei, Lou Meiyue, Matsumoto Chihiro, Zhang Weiliyun, Baba Hideo, Iwatsuki Masaaki
Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Ann Surg Oncol. 2025 Mar 27. doi: 10.1245/s10434-025-17247-3.
Imatinib (IM), a tyrosine kinase inhibitor (TKI), is the first-line treatment for patients with gastrointestinal stromal tumors (GISTs). However, its efficacy is limited due to acquired resistance induced by secondary KIT mutations in most patients with GIST. Furthermore, new challenges have emerged following the clarification that KIT-independent GISTs exhibit strong resistance to small molecule inhibitors targeting KIT/ platelet-derived growth factor receptor alpha (PDGFRA). Therefore, investigating the underlying therapeutic targets for imatinib-resistant GISTs is urgently necessitated.
Through both in vitro and in vivo experiments, along with the analysis of alterations in the FBXW7-MCL1 axis and the YAP/TAZ-CCND1 pathway in patients with GISTs, before and after IM treatment.
MCL1 overexpression and activation of the YAP/TAZ-CCND1 pathway are induced in IM-resistant GIST cells and post-IM GIST samples. AT101, a BCL-2 inhibitor, exerts a pro-apoptotic effect on GIST cells by suppressing MCL1 overexpression, and the combination therapy of AT101 and IM exerts a stronger pro-apoptotic effect through modulation of IM activity regulated by the FBXW7-MCL1 axis. Furthermore, the suppression of AT101 on GIST growth and metastasis, by targeting the YAP/TAZ-CCND1 pathway, was confirmed through xenograft and metastasis mouse models. Notably, the antitumor activity of AT101 is maintained regardless of the IM sensitivity of GIST cells, whereas AT101 enhances and restores IM activities in both GIST-T1 and IM-resistant GIST cells.
AT101 exerts a strong antitumor activity by targeting both the FBXW7-MCL1 axis and the YAP/TAZ-CCND1 pathway, suggesting that AT101 monotherapy, and its combination with IM, are worth further investigating in clinical trials.
伊马替尼（IM）是一种酪氨酸激酶抑制剂（TKI），是胃肠道间质瘤（GIST）患者的一线治疗药物。然而，由于大多数GIST患者中继发KIT突变导致获得性耐药，其疗效有限。此外，在明确非KIT依赖型GIST对靶向KIT/血小板衍生生长因子受体α（PDGFRA）的小分子抑制剂表现出强烈耐药性之后，新的挑战出现了。因此，迫切需要研究伊马替尼耐药GIST的潜在治疗靶点。
通过体外和体内实验，以及分析GIST患者在IM治疗前后FBXW7-MCL1轴和YAP/TAZ-CCND1途径的变化。
在伊马替尼耐药的GIST细胞和伊马替尼治疗后的GIST样本中，诱导了MCL1过表达和YAP/TAZ-CCND1途径的激活。BCL-2抑制剂AT101通过抑制MCL1过表达对GIST细胞发挥促凋亡作用，AT101与IM的联合治疗通过调节由FBXW7-MCL1轴调控的IM活性发挥更强的促凋亡作用。此外，通过异种移植和转移小鼠模型证实了AT101通过靶向YAP/TAZ-CCND1途径对GIST生长和转移的抑制作用。值得注意的是，无论GIST细胞对伊马替尼的敏感性如何，AT101的抗肿瘤活性均得以维持，而AT101在GIST-T1细胞和伊马替尼耐药的GIST细胞中均增强并恢复了伊马替尼的活性。
AT101通过靶向FBXW7-MCL1轴和YAP/TAZ-CCND1途径发挥强大的抗肿瘤活性，表明AT101单药治疗及其与IM的联合治疗值得在临床试验中进一步研究。
