A class of compounds called proteasome inhibitors that include bortezomib and carfilzomib -- both approved by the U.S. Food and Drug Administration -- have been effective at treating certain types of blood cancers. The drugs work by jamming some of cancer cells' machinery to induce cell death. But the drugs have been limited by cancer cells ability to develop resistance, as well as the inhibitors inability to fight solid tumors effectively. Studies have suggested that resistance could be linked to a protein called Nrf1.
. Carolyn Bertozzi and colleagues, through studying NGLY1 deficiency, a seemingly unrelated condition, may have hit upon an approach to do this.
‘Blocking the NGLY1 gene from activating Nrf1 will allow proteasome inhibitors to target cancer cells without developing drug resistance.’
The researchers were investigating how lacking the enzyme NGLY1 causes a host of debilitating symptoms. They found that NGLY1 is responsible for activating Nrf1, the protein that is suspected of weakening proteasome inhibitors' effectiveness against cancer. Further testing showed that dampening NGLY1 allowed a proteasome inhibitor to continue doing its work killing cancer cells without interference from Nrf1. This finding, the authors note, holds great promise for the development of combination therapeutics for blood cancers in the future.