UT Southwestern faculty say they have discovered what appears to be an Achilles’ heel in ovarian cancers, as well as new biomarkers that could point to which patients are the best candidates for possible new treatments. Their results suggest ribosome MARylation (the catalytic activity of mono-ADP-ribosyl-ates), promotes protein homeostasis in cancers by fine-tuning protein synthesis and preventing toxic protein aggregation.
Their findings were published in the journal Cell. The research was led by W. Lee Kraus, Ph.D., Professor of Obstetrics and Gynecology and Pharmacology and a member of the Harold C. Simmons Comprehensive Cancer Center.
“Many researchers are trying to find dependencies in cancers by asking why a cancer cell amplifies a gene, increases the levels of a protein, or upregulates a critical cellular pathway. These changes give that cancer a selective advantage, but at the same time they can become an Achilles’ heel – something that, if the alteration was blocked, would kill the cancer or stop its growth,” Kraus said.
Kraus and his team, including lead author and postdoctoral researcher Sridevi Challa, PhD, found that ovarian cancers massively amplify an enzyme, NMNAT-2, that makes NAD+—the substrate PARPs, enzymes that chemically modify proteins with ADP-ribose. In this study, the team found that PARP-16, uses NAD+ to modify ribosomes, the protein synthesizing machines of the cell.
A challenge for this work was that a single ADP-ribose group attached to a protein is difficult to detect. Kraus and his team overcame this problem by developing a synthetic mono(ADP-ribose) detection reagent made up of natural protein domains fused together, which can be used to detect ADP-ribosylated proteins in cells and patient samples.
In collaboration with UT Southwestern clinicians, led by Jayanthi Lea, M.D., professor of Obstetrics and Gynecology and member of the Simmons Cancer Center, Kraus and his team screened human ovarian cancer patient samples using the mono(ADP-ribose) detection reagent to identify those with low or high levels of mono(ADP-ribose).
“We were able to show that when ribosomes are mono(ADP-ribosyl)ated in ovarian cancer cells, the modification changes the way they translate mRNAs into proteins,” Kraus said. “The ovarian cancers amplify NMNAT-2 to increase the levels of NAD+ available for PARP-16 to mono(ADP-ribosyl)ate ribosomes, giving them a selective advantage by allowing them to fine-tune the levels of translation and prevent toxic protein aggregation. But that selective advantage also becomes their Achilles’ heel. They’re addicted to NMNAT-2, so inhibition or reduction of NMNAT-2 inhibits the growth of the cancer cells.”
This study identified mono (ADP-ribose) and NMNAT-2 as potential biomarkers for ovarian cancers, which may allow clinicians to determine which ovarian cancer patients may respond well and which will not. Even more ovarian cancer patients might do well if an inhibitor is developed for PARP-16, which blocks ribosome mono (ADP-ribosyl)ation.
Kraus said medical science has had great success in developing FDA-approved PARP-1 inhibitors, and an inhibitor for PARP-16 is likely.
“No PARP-16 inhibitors are currently in clinical trials, but labs in academia and the pharmaceutical industry are developing specific and potent inhibitors of PARP-16. Such a drug could be an effective therapeutic for treating ovarian cancers,” he said.