Cancer Center investigator targets key enzyme complex to treat KRAS-mutated lung cancer

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.”