Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy.
Exploiting Protein Translation Dependence in Multiple Myeloma with Omacetaxine-Based Therapy.
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DOI：
10.1158/1078-0432.ccr-20-2246
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发表时间：
2021-02-01
期刊：
影响因子：
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通讯作者：
Sherbenou DW
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作者：
Walker ZJ;Idler BM;Davis LN;Stevens BM;VanWyngarden MJ;Ohlstrom D;Bearrows SC;Hammes A;Smith CA;Jordan CT;Mark TM;Forsberg PA;Sherbenou DW
对蛋白酶体抑制剂、免疫调节药物（IMiD）和达雷妥尤单抗耐药的多发性骨髓瘤（MM）患者的预后极差。即使是B细胞成熟抗原（BCMA）特异性嵌合抗原受体（CAR）T细胞疗法也只能在患者死于疾病之前提供暂时的益处。在这份报告中，我们询问MM细胞的独特敏感性的替代策略，阻断蛋白质翻译omacetaxine。我们测定了原发性MM患者样本的蛋白质翻译水平（n = 17）和对omacetaxine的敏感性（n = 51）。在体外、离体和体内评价了奥美他辛和IMiD之间的协同作用。通过蛋白质组学分析研究了潜在的机制。几乎普遍地，与正常骨髓细胞相比，原代患者MM细胞表现出>2.5倍的蛋白质翻译速率增加。用奥美他辛离体处理导致活MM细胞减少>50%。在该队列中，高水平的翻译作为患者MM细胞对omacetaxine敏感性的生物标志物。出乎意料的是，omacetaxine在体外MM细胞系中表现出与IMiD的协同作用。此外，在IMiD耐药复发患者样本中，omacetaxine/IMiD联合治疗使MM细胞对IMiD重新致敏。蛋白质组学分析发现，omacetaxine/IMiD联合治疗对IRF 4/c-MYC通路产生双重打击，这对MM存活至关重要。总体而言，蛋白翻译抑制剂代表了一种潜在的骨髓瘤治疗新药类别，并为在复发性/难治性MM患者中开展奥美他辛单药治疗和与IMiD联合治疗的临床试验提供了依据。
The prognosis of patients with multiple myeloma (MM) who are resistant to proteasome inhibitors, immunomodulatory drugs (IMiDs), and daratumumab is extremely poor. Even B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cell therapies provide only a temporary benefit before patients succumb to their disease. In this report, we interrogate the unique sensitivity of MM cells to the alternative strategy of blocking protein translation with omacetaxine. We determined protein translation levels (n = 17) and sensitivity to omacetaxine (n = 51) of primary MM patient samples. Synergy was evaluated between omacetaxine and IMiDs in vitro, ex vivo, and in vivo. Underlying mechanism was investigated via proteomic analysis. Almost universally, primary patient MM cells exhibit >2.5-fold increased rates of protein translation compared to normal marrow cells. Ex vivo treatment with omacetaxine resulted in >50% reduction in viable MM cells. In this cohort, high levels of translation serve as a biomarker for patient MM cell sensitivity to omacetaxine. Unexpectedly, omacetaxine demonstrated synergy with IMiDs in MM cell lines in vitro. In addition, in an IMiD-resistant relapsed patient sample, omacetaxine/IMiD combination treatment re-sensitized the MM cells to the IMiD. Proteomic analysis found that the omacetaxine/IMiD combination treatment produced a double-hit on the IRF4/c-MYC pathway, which is critical to MM survival. Overall, protein translation inhibitors represent a potential new drug class for myeloma treatment and provide a rationale for conducting clinical trials with omacetaxine alone and in combination with IMiDs for patients with relapsed/refractory MM.