Insights from a rare genetic disease may help treat multiple myeloma

October 25, 2017, American Chemical Society
A protein called Nrf1 (shown in white in these mouse cells) can hamper promising drugs for blood cancers, but now researchers have found a possible workaround to shut Nrf1 down. Credit: The American Chemical Society

A new class of drugs for blood cancers such as leukemia and multiple myeloma is showing promise. But it is hobbled by a problem that also plagues other cancer drugs: targeted cells can develop resistance. Now scientists, reporting in ACS Central Science, have found that insights into a rare genetic disease known as NGLY1 deficiency could help scientists understand how that resistance works—and potentially how drugs can outsmart it.

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 . The drugs work by jamming some of ' machinery to induce cell death. But the drugs have been limited by cancer cells ability to development 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. When proteasome inhibitors go into action, Nrf1 is spurred into overdrive to restore the cells' normal activities and keep them alive. If researchers could figure out how to block Nrf1, they might be able to address the resistance problem. Carolyn Bertozzi and colleagues, through studying NGLY1 deficiency, a seemingly unrelated condition, may have hit upon an approach to do this.

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 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.

Explore further: A rare disease inspires a new way to attack cancer

More information: Frederick M. Tomlin et al. Inhibition of NGLY1 Inactivates the Transcription Factor Nrf1 and Potentiates Proteasome Inhibitor Cytotoxicity, ACS Central Science (2017). DOI: 10.1021/acscentsci.7b00224

Related Stories

A rare disease inspires a new way to attack cancer

October 25, 2017
Some of the most promising new treatments for blood cancers, drugs called proteasome inhibitors, have a problem: For reasons that researchers are still working to fully understand, cancer cells can build up a resistance to ...

Researchers identify key elements of cellular response to proteasome dysfunction

August 16, 2016
Maintaining appropriate levels of proteins within cells largely relies on a cellular component called the proteasome, which degrades unneeded or defective proteins to recycle the components for the eventual assembly of new ...

Naturally occurring mechanism of cancer drug-resistance may itself be a treatment target

December 27, 2016
The use of proteasome inhibitors to treat cancer has been greatly limited by the ability of cancer cells to develop resistance to these drugs. But Whitehead Institute researchers have found a mechanism underlying this resistance—a ...

TJP1 protein may identify multiple myeloma patients most likely to benefit from proteasome inhibitors

April 28, 2016
A gene known as TJP1 (tight junction protein 1) could help determine which multiple myeloma patients would best benefit from proteasome inhibitors such as bortezomib, as well as combination approaches to enhance proteasome ...

Cellular recycling complexes may hold key to chemotherapy resistance

September 2, 2015
Altering the protein recycling complexes in human cells, including cancer cells, allows the cells to resist treatment with a class of drugs known as proteasome inhibitors, according to Whitehead Institute scientists.

Boosting immune cell memory to improve vaccines and cancer immunotherapy

August 28, 2017
Vaccines and cancer immunotherapies do essentially the same thing: They boost a person's immune system, better enabling it to fight an offender, be it microbe or malignancy. Both approaches focus on CD8+ T cells, a type of ...

Recommended for you

Cancer risk associated with key epigenetic changes occurring through normal aging process

February 22, 2018
Some scientists have hypothesized that tumor-promoting changes in cells during cancer development—particularly an epigenetic change involving DNA methylation—arise from rogue cells escaping a natural cell deterioration ...

Putting black skin cancer to sleep—for good

February 22, 2018
An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes ...

NEJM reports positive results for larotrectinib against TRK-fusion cancer

February 22, 2018
In 2013, the labs of University of Colorado Cancer Center investigator Robert C. Doebele, MD, PhD, and Dana-Farber Cancer Institute investigator Pasi A. Jänne, MD, PhD reported in Nature Medicine the presence of TRK gene ...

New therapeutic gel shows promise against cancerous tumors

February 21, 2018
Scientists at the UNC School of Medicine and NC State have created an injectable gel-like scaffold that can hold combination chemo-immunotherapeutic drugs and deliver them locally to tumors in a sequential manner. The results ...

Five novel genetic changes linked to pancreatic cancer risk

February 21, 2018
In what is believed to be the largest pancreatic cancer genome-wide association study to date, researchers at the Johns Hopkins Kimmel Cancer Center and the National Cancer Institute, and collaborators from over 80 other ...

Similarities found in cancer initiation in kidney, liver, stomach, pancreas

February 21, 2018
Recent research at Washington University School of Medicine in St. Louis demonstrated that mature cells in the stomach sometimes revert back to behaving like rapidly dividing stem cells. Now, the researchers have found that ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.