Yang Haeun, Li Vladimir, Park Su Jung, Cheon Sang Won, Lorant Anne, Mazumder Aloran, Lee Jin Young, Orlikova-Boyer Barbora, Cerella Claudia, Christov Christo, Kirsch Gilbert, Olberg Dag Erlend, Bormans Guy, Kang Hyoung Jin, Han Byung Woo, Schnekenburger Michael, Diederich Marc
Research Institute of Pharmaceutical Sciences and Natural Products Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
Laboratoire de Biologie Moléculaire et Cellulaire du Cancer, 1210, Luxembourg, Luxembourg.
Clin Epigenetics. 2025 Jul 16;17(1):125. doi: 10.1186/s13148-025-01921-0.
Chronic myeloid leukemia (CML) remains a therapeutic challenge, particularly in patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) such as imatinib. Here, we present the first demonstration of the potent anti-leukemic activity of the histone deacetylase (HDAC) inhibitor martinostat in both TKI-sensitive and TKI-resistant CML.
Structural and biochemical analyses confirmed the efficient and selective binding of martinostat to HDAC isoenzyme ligand-binding pockets, resulting in histone and tubulin hyperacetylation in both imatinib-sensitive and resistant CML cells, outperforming vorinostat, a clinically used HDAC inhibitor (HDACi). It selectively impaired CML cell proliferation and viability and induced apoptosis across various CML models, including resistant cell models and patient blasts, with minimal toxicity to healthy cells and low developmental toxicity in zebrafish. In addition to its single-agent efficacy, martinostat demonstrated enhanced anticancer effects when combined with imatinib, both in vitro and in vivo, significantly reducing tumor growth in resistant CML xenograft models. Mechanistically, mRNA-seq data showed that martinostat disrupted key survival signaling pathways and amplified apoptotic responses, contributing to its anticancer activity.
These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.
慢性髓性白血病（CML）仍然是一个治疗挑战，尤其是对于那些对伊马替尼等标准酪氨酸激酶抑制剂（TKIs）产生耐药性的患者。在此，我们首次证明了组蛋白去乙酰化酶（HDAC）抑制剂马替司他在TKI敏感和TKI耐药的CML中均具有强大的抗白血病活性。
结构和生化分析证实马替司他能有效且选择性地结合HDAC同工酶配体结合口袋，导致伊马替尼敏感和耐药的CML细胞中组蛋白和微管蛋白高度乙酰化，其效果优于临床使用的HDAC抑制剂（HDACi）伏立诺他。它能选择性地损害CML细胞增殖和活力，并在各种CML模型（包括耐药细胞模型和患者原始细胞）中诱导凋亡，对健康细胞毒性极小，在斑马鱼中发育毒性低。除了单药疗效外，马替司他在体外和体内与伊马替尼联合使用时均显示出增强的抗癌效果，显著降低了耐药CML异种移植模型中的肿瘤生长。从机制上讲，mRNA测序数据表明马替司他破坏了关键的生存信号通路并增强了凋亡反应，从而促成了其抗癌活性。
这些发现突出了马替司他作为一种选择性、低毒性HDACi的潜力，与TKIs联合使用可为克服CML中的耐药性并改善治疗结果提供有效策略。
