Bishop Ryan T, Li Tao, Sudalagunta Praneeth, Nasr Mostafa, Nyman Karl J, Alugubelli Raghunandan R, Meads Mark, Frieling Jeremy, Nerlakanti Niveditha, Tauro Marilena, Fang Bin, Grant Steven, Koomen John, Silva Ariosto S, Shain Kenneth H, Lynch Conor C
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612.
Haematologica. 2025 Jun 1;110(6):1351-1367. doi: 10.3324/haematol.2024.285587. Epub 2024 Dec 5.
Multiple myeloma (MM) patients are often refractory to targeted therapies including proteasome inhibitors. 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 resistance to proteasome inhibitors. Genetic or pharmacological blockade of ASAH1 remarkably restored sensitivity to proteasome inhibitors and protected mice from resistant MM progression in vivo. Mechanistically, ASAH1 depletion of ceramide promoted SET inhibition of PP2A phosphatase activity, thus facilitating 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 patients' MM cells. These preclinical studies suggest that ASAH1 may be a potential therapeutic target for the treatment of relapsed/refractory MM.
多发性骨髓瘤（MM）患者通常对包括蛋白酶体抑制剂在内的靶向治疗具有耐药性。在此，对672例新诊断或复发/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是对蛋白酶体抑制剂耐药的关键调节因子。对ASAH1进行基因或药物阻断可显著恢复对蛋白酶体抑制剂的敏感性，并在体内保护小鼠免受耐药性MM进展的影响。从机制上讲，ASAH1缺失导致的神经酰胺减少促进了SET对PP2A磷酸酶活性的抑制，从而促进了促生存蛋白MCL-1和BCL-2表达和活性的增加。我们在人类MM数据集以及离体患者的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的潜在治疗靶点。
