A Link Between Tumor Metabolism and Drug Efficacy in Cancer Cells May Help Advance Precision Chemotherapy

The finding, published in Nature Communications, is a "mechanistic bridge" to targeted therapy

STONY BROOK, NY, December 17, 2025 - Chemotherapy drugs that target cancer cells without damaging normal cells remains one of the key goals of precision medicine in cancer treatment. The challenge is designing drugs that do this effectively. An international research team, including Peter J. Tonge, PhD, of Stony Brook University, has demonstrated a connection between drug efficacy and tumor metabolism in an established target of human cancers that provides a mechanistic bridge between tumor metabolism and drug engagement in cancer cells. The research findings are highlighted in a paper published in Nature Communications.

The study focuses on a gene-regulating protein called PRMT5 (protein arginine methyl transferase 5), a long-time top target for drug discovery. In normal cells, PRMT5 interacts with a molecule called SAM. However, in the tumor cells of approximately 10 to 15 percent of all cancers, a mutation to the gene MTAP leads to PRMT5 interacting with the molecule MTA. This creates a significant vulnerability for targeting cancer cells with a mutation to MTAP while leaving normal cells unaffected.

To summarize the approach, the researchers developed a strategy to quantify the interaction of compounds that specifically inhibit PRMT5 when it is bound to MTA and not to SAM. This is the form of PRMT5 in tumor cells with the mutated MTAP gene. To do this, they used a well-known biosensor called NanoBRET.

"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," says co-senior author Peter J. Tonge, PhD, Distinguished Professor in the Department of Chemistry in the School of Arts and Sciences at Stony Brook University, and a Visiting Professor in the Department of Biomedical Genetics at the University of Rochester.

Tonge, who played a role in analyzing the data from the study, is also an adjunct research member of the Stony Brook Cancer Center under the 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 explains.

A new technology and collaboration

The research is a collaboration between Stony Brook University's Center for Advanced Discovery of Drug Action, the University of Oxford's Centre for Medicines Discovery, Boston University, and the Promega Corporation.

Key to the findings is the use of Promega's bioluminescent NanoBRET^® Target Engagement (TE) technology, which is designed to characterize inhibitors that selectively target cancer cells without harming noncancerous ones.

The University of Oxford team designed and developed CBH-002, a cell-permeable BRET probe that binds to genetically encoded PRMT5-NanoLuc biosensor to report drug target engagement in live cells.

According to Dr. Elizabeth Mira Rothweiler, Postdoctoral Researcher, Centre for Medicines Discovery at the University of Oxford, and co-first author: "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."

"To our knowledge, this is the first time anyone has characterized this type of uncompetitive inhibitor mechanism directly in live cells," adds Dr. Ani Michaud, Senior Research Scientist at Promega and co-first author.

The biosensor also enabled the team to examine, in living cells, how different PRMT5 inhibitors act under specific metabolic conditions to make some types of tumors vulnerable.

"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," adds Kilian Huber, Associate Professor, Centre for Medicines Discovery and co-senior author. "It's like turning on the lights inside the cell so we can finally see which key actually fits the lock."

Several scientific organizations and agencies supported the research, including the National Institutes of Health (NIH), under NIH grant GM149297.