Myeloma Resistance to Proteasome Inhibitors May Boost Sensitivity to Other Drug Classes

Researchers have discovered a mechanism underlying the development of treatment resistance to proteasome inhibitors in multiple myeloma. Surprisingly, the mechanism also was linked to a complete switch in the genetic profile of a tumor — opening up for the possibility that drugs with entirely different ways of acting may be effective in such cases.

The findings indicated that tumors in which parts of the proteasome, known as 19S, were found in very low levels, had a natural resistance to these types of drugs.

The study, “Suppression of 19S proteasome subunits marks emergence of an altered cell state in diverse cancers,” was published in the journal Proceedings of the National Academy of Sciences.

Proteasomes work to degrade old or faulty proteins within cells, making them crucial for cell health and survival. Because of this key role, drugs preventing the proteasome from working are, theoretically, excellent tools for killing a cancer. But, as with numerous other cancer treatments, their real-life use is limited by cancer resistance to the treatment.

The research team at  Whitehead Institute for Biomedical Research discovered the mechanism in an earlier study, where they had used genome-wide screening in combination with manipulation of proteasome components. But since many resistance mechanisms, discovered in a lab dish, do not prove to exist in human tumors, the team decided to study the relevance of their earlier finding.

“Recently, we discovered a counterintuitive mechanism by which cells can acquire resistance to proteasome inhibitors in vitro,” Peter Tsvetkov, PhD, lead author of the study and a researcher at Whitehead, said in a press release.

“Now, in this report, we show that this mechanism is at work in many human cancers. Moreover, we have determined that the mechanism is symptomatic of a broadly altered state in the cell, with a unique gene signature and newly exposed vulnerabilities that can be targeted with existing drugs,” Tsvetkov said.

The S19 part of the proteasome is a regulatory complex made up of several subunits. Researchers discovered that when one of these subunits was missing, it made the assembly of the entire complex impossible.

“This fact reinforces just how complex the mechanisms of resistance to chemotherapy can be,” said Luke Whitesell, MD, a senior author of the PNAS paper and senior scientist at Whitehead Institute.

In cells from patients with multiple myeloma, the suppressed production of the 19S subunits could be linked to poor outcomes among those treated with the proteasome inhibitor Velcade (bortezomib).

But the researchers also found that, in tumors with suppressed proteasome subunit production, the entire gene signature of the cell was altered. This unexpected finding makes it possible to look for specific gene activity that renders a tumor vulnerable to other drug types, including those already in clinical use.

The insight may help researchers classify patients for treatment and clinical trials.