Abstract
Multiple myeloma (MM) is an incurable cancer caused by malignant transformation of plasma cells. Transforming growth factor-β activated kinase 1 (MAP3K7, TAK1) is a major regulator of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. Both NF-κB and MAPK control expression of genes with vital roles for drug resistance in MM. TAK1 is an attractive drug target as it switches these survival pathways to cell death. Our analysis showed that patients with high MAP3K7 expression in the tumor had shorter overall and progression free survival. The TAK1-inhibitors NG25 and 5Z-7-oxozeaenol (5Z-7) were cytotoxic to MM cell lines and patient cells. NG25 reduced expression of MYC and E2F controlled genes, involved in tumor cell growth, cell cycle progression and drug resilience. TAK1 can be activated by genotoxic stress. NG25 and 5Z-7 induced both synergistic and additive cytotoxicity in combination with the alkylating agent melphalan. Melphalan activated TAK1, NF-κB, and the MAPKs p38 and c-Jun N-terminal kinase (JNK), as well as a transcriptional UV-response. This was blocked by NG25, and instead apoptosis was activated. MM induce elevated bone-degradation resulting in myeloma bone disease (MBD), which is the main cause of disability and morbidity in MM patients. NG25 and 5Z-7 reduced differentiation and viability of human bone degrading osteoclasts, suggesting that TAK1-inhibition can have a double beneficial effect for patients. In sum, TAK1 is a promising drug target for MM treatment.
Highlights
Multiple myeloma (MM) is the second most common hematological malignancy worldwide
transforming growth-factor-β activated kinase 1 (TAK1)-inhibitors are cytotoxic to MM cell lines alone and in combination with melphalan
We present findings showing that TAK1-inhibitors are cytotoxic to multiple myeloma cells and OC
Summary
Multiple myeloma (MM) is the second most common hematological malignancy worldwide. It is characterized by malignant transformation of clonal plasma cells in the bone marrow accompanied by secretion of monoclonal immunoglobulins, and cancer-induced bone degradation (myeloma bone disease, MBD). The disease is still incurable due to minimal residual disease (MRD), development of drug resistance and relapse. A common treatment strategy in multiple myeloma is induction of DNA damage in the MM cells caused by DNA-damaging agents, such as melphalan. They are associated with side effects for the patients and they eventually develop drug resistance [2]
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