Acid ceramidase controls proteasome inhibitor resistance and is a novel therapeutic target for the treatment of relapsed / refractory multiple myeloma
Ryan T. Bishop,
Tao Li,
Praneeth Sudalagunta,
Mostafa Nasr,
Karl J. Nyman,
Raghunandan R. Alugubelli,
Mark Meads,
Jeremy Frieling,
Niveditha Nerlakanti,
Marilena Tauro,
Bin Fang,
Steven Grant,
John Koomen,
Ariosto S. Silva,
Kenneth H. Shain,
Conor C. Lynch
Affiliations
Ryan T. Bishop
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Tao Li
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Praneeth Sudalagunta
Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Mostafa Nasr
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL
Karl J. Nyman
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL
Raghunandan R. Alugubelli
Collaborative Data Services Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Mark Meads
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Jeremy Frieling
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Niveditha Nerlakanti
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL
Marilena Tauro
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Bin Fang
Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Steven Grant
Virginia Commonwealth University (VCU) Massey Cancer Center Richmond, VA
John Koomen
Chemical Biology and Molecular Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Ariosto S. Silva
Department of Metabolism and Physiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Kenneth H. Shain
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA; Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
Conor C. Lynch
Department of Tumor Metastasis and Microenvironment., H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612
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).
