An international team of researchers, including Peter J. Tonge, PhD, from Stony Brook University, has identified a link between tumor metabolism and the effectiveness of chemotherapy drugs in cancer cells. The findings are published in Nature Communications.
The study examines the gene-regulating protein PRMT5, which is a significant target for drug development in cancer treatment. In normal cells, PRMT5 interacts with the molecule SAM. However, about 10 to 15 percent of cancers have a mutation in the MTAP gene that causes PRMT5 to interact with MTA instead. This difference creates an opportunity to target cancer cells with this mutation while sparing healthy cells.
Researchers developed a method using NanoBRET technology to measure how compounds inhibit PRMT5 when it is bound to MTA—a condition found only in tumor cells with mutated MTAP genes. This approach aims to increase drug selectivity and reduce harm to normal tissue.
“Selectivity is one of the most critical challenges in cancer therapy, as most treatments also damage healthy cells, and this leads to dose-limiting toxicities and reduced therapeutic effectiveness,” said Peter J. Tonge, PhD, Distinguished Professor at Stony Brook University and Visiting Professor at the University of Rochester.
Tonge contributed data analysis for the study and is affiliated with the Stony Brook Cancer Center’s Imaging, Biomarker Discovery and Engineering Sciences Program.
“Our work shows a new class of tumor-specific drugs that acts uncompetitively or cooperatively – that is to say only binds to the enzyme complex related to the cancer – with a metabolite that accumulates only in cancer cells, limiting activity to tumor tissue,” Tonge explained.
The research involved collaboration among Stony Brook University’s Center for Advanced Discovery of Drug Action, University of Oxford’s Centre for Medicines Discovery, Boston University, and Promega Corporation.
A key aspect was Promega’s bioluminescent NanoBRET Target Engagement technology used for characterizing inhibitors that selectively affect cancerous but not noncancerous cells. The Oxford team created CBH-002—a probe designed to bind genetically encoded PRMT5-NanoLuc biosensors—to monitor drug engagement within live cells.
“CBH-002 could measure various PRMT5 inhibitor types in live cells, prompting us to test its sensitivity to the cofactor SAM. When we discovered the probe’s ability to sense metabolite levels, it established its utility as a metabolic biosensor. Through collaboration with Promega, we demonstrated how MTA influences drug selectivity, revealing why certain inhibitors are so effective in MTAP-deleted cancers,” said Dr. Elizabeth Mira Rothweiler from Oxford and co-first author on the paper.
“To our knowledge, this is the first time anyone has characterized this type of uncompetitive inhibitor mechanism directly in live cells,” added Dr. Ani Michaud from Promega Corporation and co-first author.
Using this biosensor allowed researchers to observe how different PRMT5 inhibitors function under specific metabolic conditions inside living tumor cells.
“This provides unprecedented insight into why certain inhibitors are much more effective in cancers lacking MTAP and paves the way for highly targeted cancer treatment in the future,” said Kilian Huber from Oxford’s Centre for Medicines Discovery and co-senior author on the study. “It’s like turning on the lights inside the cell so we can finally see which key actually fits the lock.”
Funding support came from several scientific organizations including grants from National Institutes of Health (NIH).