Researchers at UT Southwestern have discovered a potential “Achilles’ heel” in ovarian cancer cells, and a new biomarker that may open up more avenues for targeted therapies.
The study, published in the journal Cell, was led by W. Lee Kraus, PhD, Professor of Obstetrics and Gynecology and Pharmacology at UT Southwestern. Sridevi Challa, PhD, a 2020 OCRA grant recipient, was lead author of the study.
Says Dr. Kraus, “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.”
Dr. Kraus and his team discovered that ovarian cancers significantly amplify an enzyme, called NMNAT-2, that makes NAD+ — an underlying mechanism of a family of enzymes called PARPs. PARPs chemically modify proteins with ADP-ribose, which comes from NAD+. One member of the PARP family — PARP-16 — was found to use NAD+ to modify ribosomes, which are the protein synthesizers of the cell and, researchers hypothesized, key to the growth of a subset of ovarian cancers.
By developing a synthetic mono(ADP-ribose), researchers were able to detect ADP-ribosylated proteins in cells and patient samples, and subsequently showed that “…when ribosomes are mono(ADP-ribosyl)ated in ovarian cancer cells, the modification changes the way they translate mRNAs into proteins.”
The study identified mono(ADP-ribose) and NMNAT-2 as potential ovarian cancer biomarkers, which could play a crucial role in determining which ovarian cancer patients may respond to certain treatments.
Says Dr. Kraus, “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.”
Excitingly, these results also opens the door to developing PARP-16 inhibitors, which may be an effective treatment option for a subset of ovarian cancer patients.
Read more at “UT Southwestern finds crucial new molecular mechanisms and biomarkers in ovarian cancer,” and view the abstract in Cell.