Nakamura Kazuki, Ito Yasufumi, Takenouchi Senri, Nakagawa-Saito Yurika, Suzuki Shuhei, Togashi Keita, Sugai Asuka, Mitobe Yuta, Sonoda Yukihiko, Kitanaka Chifumi, Okada Masashi
Departments of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
Departments of Neurosurgery, Yamagata University School of Medicine, Yamagata, Japan.
Anticancer Res. 2025 Jul;45(7):2917-2924. doi: 10.21873/anticanres.17659.
BACKGROUND/AIM: Glioblastoma is a highly aggressive brain tumor characterized by poor prognosis and inevitable recurrence following standard therapy. Glioma stem cells (GSCs), a subpopulation with enhanced tumor-initiating potential and resistance to conventional treatments, are thought to drive tumor recurrence and progression. The c-Jun N-terminal kinase (JNK) signaling pathway plays a key role in maintaining the stem-like properties of GSCs. While JNK has emerged as a potential therapeutic target, the effectiveness of upstream targeting at the level of MKK4 and MKK7, the MAP2Ks that activate JNK, has not been fully explored in this context.
The effects of BSJ-04-122 on the viability of normal human fibroblasts and matched pairs of GSCs and their isogenic, differentiated counterparts as well as on the JNK activity, self-renewal (glioma stem cell marker expression and sphere-forming ability) and tumor-initiating capacity of GSCs were examined.
At concentrations that did not affect the viability of normal fibroblasts, BSJ-04-122 effectively inhibited JNK activity and reduced the expression of stem cell markers in GSCs and induced cell death more efficiently in GSCs than in their differentiated counterparts. Furthermore, the capacity of GSCs that survived the BSJ-04-122 treatment to form spheres and initiate tumors was impaired.
BSJ-04-122 is a first-in-class covalent dual inhibitor of MKK4/7 that selectively targets GSCs by inhibiting JNK signaling, leading to cell death or loss of stem-like properties. These findings support a therapeutic strategy that combines BSJ-04-122 to eliminate GSCs with conventional therapies targeting non-stem glioblastoma cells, offering a rational and potentially effective approach for treating this aggressive brain tumor.
背景/目的：胶质母细胞瘤是一种高度侵袭性的脑肿瘤，其特征是预后不良且标准治疗后不可避免地复发。胶质瘤干细胞（GSCs）是一群具有增强的肿瘤起始潜能和对传统治疗耐药的亚群，被认为驱动肿瘤复发和进展。c-Jun氨基末端激酶（JNK）信号通路在维持GSCs的干细胞样特性中起关键作用。虽然JNK已成为一个潜在的治疗靶点，但在这种情况下，尚未充分探索在MKK4和MKK7（激活JNK的丝裂原活化蛋白激酶激酶2）水平进行上游靶向治疗的有效性。
研究了BSJ-04-122对正常人成纤维细胞、配对的GSCs及其同基因分化对应物的活力的影响，以及对GSCs的JNK活性、自我更新能力（胶质瘤干细胞标志物表达和球形成能力）和肿瘤起始能力的影响。
在不影响正常成纤维细胞活力的浓度下，BSJ-04-122有效抑制JNK活性，降低GSCs中干细胞标志物的表达，并且与分化对应物相比，在GSCs中诱导细胞死亡的效率更高。此外，经BSJ-04-122处理后存活的GSCs形成球体和引发肿瘤的能力受损。
BSJ-04-122是首个MKK4/7共价双重抑制剂，通过抑制JNK信号通路选择性靶向GSCs，导致细胞死亡或干细胞样特性丧失。这些发现支持一种治疗策略，即联合使用BSJ-04-122消除GSCs与针对非干细胞性胶质母细胞瘤细胞的传统疗法，为治疗这种侵袭性脑肿瘤提供了一种合理且可能有效的方法。
