Researchers from Uppsala University show in a new study that inhibition of the EZH2 protein can reduce cancer cell growth in many blood cancer myeloma. The decrease is caused by changes in the metabolism of cancer cells. These changes can be used as indications to discriminate whether a patient undergoes treatment with EZH2 inhibition. The study was published in the journal Cell Death & Disease.
Multiple myeloma is a type of blood cancer in which immune cells grow in an uncontrolled manner in the bone marrow. The disease is very difficult to treat and is still considered unstable, so it is imperative to identify new therapeutic targets in the cancer cells.
The research group behind the new study has previously shown that several cultured myeloma cells had reduced growth and were even killed if they were treated with a substance that inhibits EZH2 protein. They now found that EZH2 inhibition also reduced cancer growth in a multiple myeloma mouse model.
“We treated mice with a cancerous type that responds to multiple human myeloma with EZH2-inhibiting material and found several signs that the treated mice had slower cancer growth than the non-treated mice This provided further evidence for the potential of EZH2 as its target for clinical intervention, “said Helena Jernberg Wiklund, a professor at the Department of Psychology, Genetics and Pathology, who led the study.
The results from the mouse model prompted the researchers to further investigate what makes the cells sensitive to EZH2 inhibition. Multiple human myeloma cells are more heterogeneous than mouse model cells and found that some types of cultured human myeloma cells were sensitive but others resisted.
To further investigate this phenomenon, the researchers used global analysis of cell metabolites in conjunction with analysis of gene activity. Sensitivity was found to be related to changes in specific metabolic pathways in the cells.
“In cells that were sensitive to EZH2 inhibition, the methionine cycle pathways were altered, an effect we did not detect in insensitive cells. This mutation was caused by a decrease in genes associated with methionine cycling,” said Helena Jernberg Wiklund.
The changes in metabolite abundance in the methionine cycle pathways could be used as indicators to discriminate whether a patient responds to EZH2 inhibition, which is critical for potential clinical use. this treatment.
Our findings provide further insight into the mechanisms behind myeloma multicellular sensitivity to EZH2 inhibition. They also make clear that global analysis of metabolites and gene activity are powerful tools and when used together, provide a better understanding of what happens in cancer cells when exposed to novel remedies. We believe our findings are relevant to both preclinical and clinical researchers, as a step toward finding new ways to treat patients with multiple myeloma. “
Helena Jernberg Wiklund, Professor, Uppsala University
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Magazine Reference:
Nylund, P., et al. (2021) Specific metabolic response indicates sensitivity to EZH2 inhibition in multiple myeloma. Cell Death & Disease. doi.org/10.1038/s41419-021-03447-8.