Wang Pei-Hong, Hu Chu-Hong, Fan Jia-Qi, He Jia-Jun, Deng Ting-Fen, Xu Yan-Li, Dai Yu-Jun, Wang Shun-Qing
Department of Hematology, Guangzhou First People's Hospital, Institute of Blood Transfusion and Hematology, Guangzhou Medical University, Guangzhou, Guangdong, 500020, China.
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.
J Transl Med. 2025 May 8;23(1):520. doi: 10.1186/s12967-025-06525-z.
Acute myeloid leukemia (AML) remains a therapeutic challenge due to drug resistance and relapse. Selinexor, an XPO1 inhibitor, shows limited efficacy as monotherapy, necessitating combination strategies. JQ1, a BET inhibitor targeting MYC, may synergize with Selinexor to enhance antileukemic effects.
AML cell lines, primary patient samples, and xenograft models (MLL-AF9, CDX, PDX) were treated with Selinexor and JQ1 alone or combined. Synergy was assessed via viability assays (Compusyn/SynergyFinder), apoptosis (flow cytometry/Western blot), and C-MYC suppression (qPCR/CRISPR). In vivo efficacy was evaluated by tumor burden (flow cytometry) and survival.
The combination demonstrated strong synergy (CI < 1, HSA > 10) across AML models, with > 80% inhibition in cell lines and primary samples. Mechanistically, it suppressed C-MYC (protein/mRNA), induced apoptosis (cleaved PARP), and arrested cell cycle. In vivo, the combination reduced leukemic burden in bone marrow, spleen, and liver, extending survival in xenografts. PDX models confirmed efficacy in primary AML cells.
Selinexor and JQ1 synergistically target AML by dual C-MYC inhibition, offering a promising strategy to overcome resistance. Further clinical evaluation is warranted.
由于耐药性和复发，急性髓系白血病（AML）仍然是一个治疗挑战。塞利尼索（Selinexor）是一种XPO1抑制剂，作为单一疗法疗效有限，因此需要联合治疗策略。JQ1是一种靶向MYC的BET抑制剂，可能与塞利尼索协同作用以增强抗白血病作用。
对AML细胞系、原发性患者样本和异种移植模型（MLL-AF9、CDX、PDX）单独或联合使用塞利尼索和JQ1进行处理。通过活力测定（Compusyn/SynergyFinder）、凋亡检测（流式细胞术/蛋白质免疫印迹法）和C-MYC抑制（定量聚合酶链反应/CRISPR）评估协同作用。通过肿瘤负荷（流式细胞术）和生存期评估体内疗效。
在所有AML模型中，联合用药均显示出强大的协同作用（协同指数<1，高协同作用评分>10），对细胞系和原发性样本的抑制率>80%。从机制上讲，它抑制C-MYC（蛋白质/信使核糖核酸），诱导凋亡（裂解的聚（ADP-核糖）聚合酶），并使细胞周期停滞。在体内，联合用药降低了骨髓、脾脏和肝脏中的白血病负担，延长了异种移植模型的生存期。PDX模型证实了对原发性AML细胞的疗效。
塞利尼索和JQ1通过双重抑制C-MYC协同靶向AML，为克服耐药性提供了一种有前景的策略。有必要进行进一步的临床评估。
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