multiple myeloma
Micrograph showing
Preclinical research has revealed a potential method of overcoming resistance to proteasome inhibitors.
By studying a rare genetic disease known as NGLY1 deficiency, researchers have gained new understanding of resistance to proteasome inhibitors.
The team found that treatment with a NGLY1 inhibitor can enhance the activity of the proteasome inhibitor carfilzomib against multiple myeloma (MM) and T-cell acute lymphoblastic leukemia (T-ALL).
Carolyn Bertozzi, PhD, of Stanford University in California, and her colleagues reported these findings in ACS Central Science.
Previous studies have suggested that proteasome inhibitor resistance could be linked to a protein called Nrf1. When proteasome inhibitors swing into action, Nrf1 is spurred into overdrive to restore cancer cells’ normal activities and keep them alive.
Researchers theorized that, if they could block Nrf1, they might be able to overcome proteasome inhibitor resistance.
Through studying NGLY1 deficiency, Dr Bertozzi and her colleagues may have hit upon an approach to do just that.
The researchers were investigating how lacking NGLY1 causes a host of debilitating symptoms, and they found that NGLY1 is responsible for activating Nrf1.
Further testing revealed that inhibiting NGLY1 eliminated interference from Nrf1 and enhanced the cytotoxicity of carfilzomib in MM and T-ALL cell lines.
The researchers treated the MM cell lines U266 and H929 with the NGLY1 inhibitor, known as WRR139, and carfilzomib and observed a significant decrease in cell survival when compared to treatment with carfilzomib alone. The team observed the same results when testing the T-ALL Jurkat cell line.
The addition of WRR139 resulted in a 2.6-fold reduction in carfilzomib’s LD50 for U266, a 2.0-fold reduction for H929, and a 1.5-fold reduction for Jurkat cells.
The researchers said these findings hold promise for the development of combination therapies for hematologic malignancies.
