TAK1-inhibitors—alone and in combination with melphalan—are cytotoxic to multiple myeloma cells, which could indicate that TAK1 is a promising drug target for the treatment of multiple myeloma, according to a study published in Oncotarget. TAK1 restricts receptor-interacting serine/threonine-protein kinase 1 dependent cell death, and targeting TAK1 with inhibitors shifts cells from pro-survival programs to cell death, according to the study.
Prior investigations have proposed targeting the kinases upstream in the signaling pathway, including TAK1, and although initial results were promising, research has been limited until now. According to the authors of the current study, the TAK1-inhibitors NG25 and 5Z-7 reduce the viability of both multiple myeloma cell lines and primary cells, and further induced both synergistic and additive cytotoxicity when used in combination with the alkylating agent melphalan.
Though melphalan activated TAK1, NF-B, and the MAPKs p38 and c-Jun N-terminal kinase, as well as a transcriptional UV-response, this was blocked by NG25, and apoptosis was activated instead. The study found that combining TAK1 inhibitors with melphalan or other DNA-damaging agents increases the cytotoxicity of the drugs synergistically.
The investigators also found that TAK1-inhibitors reduced the number and viability of osteoclasts—specialized macrophages that degrade bone—which they believe is an indicator that they have a positive effect on myeloma bone disease (MBD). MBD is a severe complication of multiple myeloma, and it results in tumor growth and pain for patients with the condition.
“TAK1-inhibitors reduce multiple myeloma cell viability and induce apoptosis through several mechanisms,” the investigators said in a prepared statement. “They potently induce cell death in combination with melphalan and reduce OC numbers and viability. TAK1 is an interesting candidate for further clinical testing as a drug target in multiple myeloma.”
According to the study authors, multiple myeloma is the second most common hematological malignancy worldwide. Overall survival for patients with multiple myeloma has improved over the past few years as novel therapeutic strategies have been introduced.
Oncotarget: TAK1-inhibitors are cytotoxic for multiple myeloma cells [news release]. EurekAlert; October 12, 2021. Accessed October 18, 2021. https://www.eurekalert.org/news-releases/929677