Role of NGLY1 in Multiple Myeloma Treatment Resistance
Researchers from Stanford University investigating the role of the enzyme NGLY1 in multiple myeloma have found that patients with myeloma who lack NGLY1 may develop resistance to certain chemotherapies. They found that NGLY1 is responsible for activating Nrf1, the protein suspected of weakening the effectiveness of proteasome inhibitors against certain cancers. Additional testing showed that dampening NGLY1 allowed a proteasome inhibitor to continue killing cancer cells without interference from Nrf1.
Carolyn Bertozzi, PhD, of Stanford University School of Humanities and Sciences, and colleagues, reporting in ACS Central Science, suggest that if researchers could develop a mechanism to block Nrf1, they may be able to address the problem of resistance to proteasome inhibitors. They noted that since NGLY1 knockdown potentiates proteasome inhibitor toxicity, a small molecule NGLY1 inhibitor may have therapeutic value in combination with drugs such as carfilzomib.
“NGLY1 inhibition prevents Nrf1 activation and represents a new therapeutic approach for cancers that depend on proteasome homeostasis,” concluded Dr. Bertozzi and colleagues.
An important finding from this study is the identification of a rare autosomal-recessive disorder characterized by inactivating mutations in both alleles of the NGLY1 gene. Patients with NGLY1 deficiency experience a variety of severe pathologies, such as developmental delays, movement disorders, seizures, alacrima, liver abnormalities, delayed bone age, and neurodegeneration.