Multiple myeloma (MM) patients are often refractory to targeted therapies including proteasome inhibitors (PIs). Here, analysis of RNA sequencing data derived from 672 patients with newly diagnosed or relapsed/refractory disease identified the acid ceramidase, ASAH1, as a key regulator of PI resistance. Genetic or pharmacological blockade of ASAH1 remarkably restored PI sensitivity and protected mice from resistant MM progression in vivo. Mechanistically, ASAH1 depletion of ceramide promoted SET inhibition of PP2A phosphatase activity thus facilitating the increased expression and activity of the pro-survival proteins, MCL-1, and BCL-2. We corroborated these findings in human MM datasets, and in ex vivo patient MM cells. These preclinical studies suggest that ASAH1 may be a potential therapeutic target for the treatment of relapsed/refractory MM (RRMM).

中文翻译：

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酸性神经酰胺酶控制蛋白酶体抑制剂耐药性，是治疗复发/难治性多发性骨髓瘤的新型治疗靶点。


多发性骨髓瘤 （MM） 患者通常对包括蛋白酶体抑制剂 （PI） 在内的靶向治疗无效。在这里，对 672 名新诊断或复发/难治性疾病患者的 RNA 测序数据进行分析，确定酸性神经酰胺酶 ASAH1 是 PI 耐药性的关键调节因子。ASAH1 的遗传或药理学阻断显着恢复了 PI 敏感性并保护小鼠在体内免受耐药性 MM 进展。从机制上讲，神经酰胺的 ASAH1 耗竭促进了 SET 对 PP2A 磷酸酶活性的抑制，从而促进了促存活蛋白 MCL-1 和 BCL-2 的表达和活性增加。我们在人类 MM 数据集和离体患者 MM 细胞中证实了这些发现。这些临床前研究表明，ASAH1 可能是治疗复发/难治性 MM （RRMM） 的潜在治疗靶点。