Cancer Center investigator targets key enzyme complex to treat KRAS-mutated lung cancer
Lung Cancer Research Foundation funds preclinical basic science research
The University of Cincinnati Cancer Center’s Tom Cunningham has received a two-year, $150,000 grant from the Lung Cancer Research Foundation (LCRF) to test approaches to neutralize an enzyme complex that plays a vital role in the growth of KRAS-mutated lung cancers.
Study details
Tom Cunningham, PhD. Photo/University of Cincinnati.
Every time a cell divides, it needs to double its nucleotides, chemical building blocks that help form RNA and DNA and play vital roles in energy and oxidoreductive balance. To produce each individual nucleotide, cells require an enzyme called phosphoribosyl pyrophosphate synthetase (PRPS).
“This is an enzyme that goes all the way back to the last universal common ancestor of life on this planet, so it’s ancient,” said Cunningham, PhD, a Cancer Center researcher and associate professor in the Department of Cancer Biology in UC’s College of Medicine. “When cells are actively growing, such as the case in cancer cells, they must increase that enzyme’s output.”
The grant builds on previously published research from Cunningham’s lab that traced the evolutionary origins of the PRPS enzyme complex and identified how this complex helps drive lymphoma growth.
“The ability to transform cells into a malignant state requires a highly capable and competent PRPS enzyme,” Cunningham said. “So the crux of the grant is that this creates a vulnerability and dependency in oncogene-expressing lung cancer cells.”
PRPS is involved in many different pathways and upregulated in various ways. Cunningham and his team will specifically work to identify the best strategy to suppress the enzyme and to identify how deregulating PRPS contributes to long-term tumor growth in KRAS-mutated lung cancers.
“For something that's part of the core infrastructure of every cell’s biochemistry for billions of years, you can’t just hit it with a sledgehammer and take it out,” Cunningham said. “So a nuanced approach is needed, and even subtle tweaks may be effective, because this enzyme conducts hundreds of billions to trillions of reactions per round of cell division. The fact that it exists in various combinations and configurations of each of the four individual components, which aren’t all simultaneously required, provides a therapeutic window for effective anticancer treatment.”
This is a collective effort I reap the reward for, but credit can more appropriately be attributed to the quality of the colleagues I’m surrounded by here.
Tom Cunningham, PhD
Solid infrastructure leads to grant funding
Cunningham said he is grateful to the LCRF and their donors for believing in his research and understanding the importance of early-stage, preclinical, basic science research. He noted previous LCRF funding has led to seminal discoveries, such as support beginning in 2012 that led to the 2025 Food and Drug Administration approval of a drug that targets NTRK-mutated lung cancers.
“You have to be very thankful that there are people willing to donate their own money to these causes,” he said. “Especially basic science causes, because a lot of times the potential isn’t realized until 10 or 20 years down the line.”
The grant also highlights the Cancer Center’s strong lung cancer research infrastructure, particularly focused on KRAS mutations. Cunningham credited support from colleagues Pier Paolo Scaglioni, Krushna Patra and Andrew Waters, and from a Cancer Center pilot grant that set up the project for success.
“This is a collective effort I reap the reward for, but credit can more appropriately be attributed to the quality of the colleagues I’m surrounded by here,” Cunningham said. “I have a really strong feeling I don’t get this grant if I don’t have people supporting me and the project by providing the expertise, tools and models needed to successfully address the ambitious aims we proposed.”
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Featured illustration at top of a multi enzyme complex. Photo/Artur Plawgo/iStock Photo.
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