Princess Margaret Cancer Centre, Toronto, Ontario M5G 1L7, Canada.
Molecular Medicine Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
Sci Transl Med. 2019 Oct 30;11(516). doi: 10.1126/scitranslmed.aax2863.
Venetoclax is a specific B cell lymphoma 2 (BCL-2) inhibitor with promising activity against acute myeloid leukemia (AML), but its clinical efficacy as a single agent or in combination with hypomethylating agents (HMAs), such as azacitidine, is hampered by intrinsic and acquired resistance. Here, we performed a genome-wide CRISPR knockout screen and found that inactivation of genes involved in mitochondrial translation restored sensitivity to venetoclax in resistant AML cells. Pharmacologic inhibition of mitochondrial protein synthesis with antibiotics that target the ribosome, including tedizolid and doxycycline, effectively overcame venetoclax resistance. Mechanistic studies showed that both tedizolid and venetoclax suppressed mitochondrial respiration, with the latter demonstrating inhibitory activity against complex I [nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase] of the electron transport chain (ETC). The drugs cooperated to activate a heightened integrated stress response (ISR), which, in turn, suppressed glycolytic capacity, resulting in adenosine triphosphate (ATP) depletion and subsequent cell death. Combination treatment with tedizolid and venetoclax was superior to either agent alone in reducing leukemic burden in mice engrafted with treatment-resistant human AML. The addition of tedizolid to azacitidine and venetoclax further enhanced the killing of resistant AML cells in vitro and in vivo. Our findings demonstrate that inhibition of mitochondrial translation is an effective approach to overcoming venetoclax resistance and provide a rationale for combining tedizolid, azacitidine, and venetoclax as a triplet therapy for AML.
维奈托克是一种特异性 B 细胞淋巴瘤 2（BCL-2）抑制剂，对急性髓系白血病（AML）具有显著疗效，但由于内在和获得性耐药，其作为单一药物或与低甲基化剂（HMAs）（如阿扎胞苷）联合应用的临床疗效受到限制。在这里，我们进行了全基因组 CRISPR 敲除筛选，发现失活参与线粒体翻译的基因可恢复耐药 AML 细胞对维奈托克的敏感性。用靶向核糖体的抗生素（包括替加环素和强力霉素）抑制线粒体蛋白合成可有效克服维奈托克耐药性。机制研究表明，替加环素和维奈托克均可抑制线粒体呼吸，后者对电子传递链（ETC）的 NADH 脱氢酶复合物 I 具有抑制活性。这两种药物协同作用激活了强烈的综合应激反应（ISR），进而抑制糖酵解能力，导致三磷酸腺苷（ATP）耗竭和随后的细胞死亡。在移植了耐药性人类 AML 的小鼠中，替加环素和维奈托克联合治疗优于单独使用任何一种药物，可降低白血病负担。在体外和体内，替加环素联合阿扎胞苷和维奈托克进一步增强了对耐药 AML 细胞的杀伤作用。我们的研究结果表明，抑制线粒体翻译是克服维奈托克耐药的有效方法，并为将替加环素、阿扎胞苷和维奈托克联合作为 AML 的三联疗法提供了依据。
