Purpose: Despite the availability of new drugs, many patients with acute myeloid leukemia (AML) do not achieve remission and outcomes remain poor. Venetoclax is a promising new therapy approved for use in combination with a hypomethylating agent or with low dose cytarabine for the treatment of newly diagnosed older AML patients or those ineligible for intensive chemotherapy. 225Actinium-lintuzumab (225Ac-lintuzumab) is a clinical stage radioimmunotherapy targeting CD33 that has shown evidence of single agent activity in relapsed/refractory AML. Increased expression of MCL-1 is a mediator of resistance to venetoclax in cancer. Experimental design: Here we investigated the potential for 225Ac-lintuzumab-directed DNA damage to suppress MCL-1 levels as a possible mechanism of reversing resistance to venetoclax in two preclinical in vivo models of AML. Results: We demonstrated that 225Ac-lintuzumab in combination with venetoclax induced a synergistic increase in tumor cell killing compared to treatment with either drug alone in venetoclax-resistant AML cell lines through both an induction of double-stranded DNA breaks (DSBs) and depletion of MCL-1 protein levels. Further, this combination led to significant tumor growth control and prolonged survival benefit in venetoclax-resistant in vivo AML models. Conclusions: There results suggest that the combination of 225Ac-lintuzumab with venetoclax may be a promising therapeutic strategy for the treatment of patients with venetoclax-resistant AML.

中文翻译：

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225Ac标记的靶向CD33的抗体可逆转急性髓样白血病模型中对Bcl-2抑制剂Venetoclax的耐药性

目的：尽管有新药可供使用，但许多急性髓细胞性白血病（AML）患者仍未获得缓解，结果仍然很差。Venetoclax是一种有前途的新疗法，已被批准与次甲基化剂或低剂量阿糖胞苷联用，用于治疗新诊断的老年AML患者或不适合进行强化学疗法的患者。225Actinium-lintuzumab（225Ac-lintuzumab）是靶向CD33的临床阶段放射免疫疗法，已证明其在复发/难治性AML中具有单药活性。MCL-1的表达增加是癌症中对Venetoclax的抗性介体。实验设计：在这里，我们研究了225Ac-lintuzumab定向DNA损伤抑制MCL-1水平的可能性，这是在两种临床前AML体内模型中逆转对Venetoclax耐药性的可能机制。结果：我们证明，与诱导静脉内双链DNA断裂（DSB）和耗竭的双链DNA均相比，与单独使用任一药物治疗耐Venetoclax的AML细胞系相比，将225Ac-lintuzumab与venetoclax组合可诱导协同增加的肿瘤细胞杀伤力。 MCL-1蛋白水平。此外，这种组合导致在耐Venetclax的体内AML模型中有效控制肿瘤生长并延长了生存期。结论：结果表明，225Ac-lintuzumab与Venetoclax的联合使用可能是治疗耐Venetoclax的AML患者的有前途的治疗策略。我们证明了225Ac-lintuzumab与venetoclax联合使用可诱导双链DNA断裂（DSBs）和MCL-耗竭，与在venetoclax耐药AML细胞系中单独使用任一药物相比，诱导肿瘤细胞杀伤的协同增加。 1蛋白质水平。此外，这种组合导致在耐威尼托克斯的体内AML模型中显着控制肿瘤生长并延长了生存期。结论：结果表明，225Ac-lintuzumab与Venetoclax的联合使用可能是治疗耐Venetoclax的AML患者的有前途的治疗策略。我们证明了225Ac-lintuzumab与venetoclax联合使用可诱导双链DNA断裂（DSBs）和MCL-耗竭，与单独使用任一药物治疗的耐venetoclax的AML细胞系相比，可协同增加肿瘤细胞的杀伤力。 1蛋白质水平。此外，这种组合导致在耐Venetclax的体内AML模型中有效控制肿瘤生长并延长了生存期。结论：结果表明，225Ac-lintuzumab与Venetoclax的联合使用可能是治疗耐Venetoclax的AML患者的有前途的治疗策略。这种组合可在耐Venetoclax的体内AML模型中显着控制肿瘤生长并延长生存期。结论：结果表明，225Ac-lintuzumab与Venetoclax的联合使用可能是治疗耐Venetoclax的AML患者的有前途的治疗策略。这种组合可在耐Venetoclax的体内AML模型中显着控制肿瘤生长并延长生存期。结论：结果表明，225Ac-lintuzumab与Venetoclax的联合使用可能是治疗耐Venetoclax的AML患者的有前途的治疗策略。