Targeting Metabolic Mechanism Restores Chemotherapy Sensitivity in Ovarian Cancer
Although many cancers can be successfully treated using platinum-based chemotherapies, which work by damaging DNA, a subset avoid cell death by repairing their own DNA. Ovarian cancers are an example. Patients whose tumors are DNA repair proficient historically face poor prognosis and their tumors commonly recur within months.
Now data from a new study done in cells and mice points to a potential metabolic target that could prevent tumor cells from repairing their own DNA, thus overcoming their resistance. The work was done by scientists from The Wistar Institute, Temple University, and their collaborators elsewhere. Details are published in a new Nature paper titled “αKG-mediated carnitine synthesis drives DNA repair via histone acetylation.” In it, they describe a metabolic process that is altered in cancer cells that makes them resistant to DNA-damaging agents. They have also identified a drug that can inhibit the pathway that may offer a strategy for overcoming chemotherapy resistance.
Specifically, the study centers on alpha-ketoglutarate (αKG), a metabolite which accumulates in DNA repair proficient ovarian tumors. First, the scientists confirmed αKG’s role in helping ovarian cancer cells repair DNA and survive chemotherapy treatment. They did this by using a CRISPR-based approach to systematically search for the enzyme that enables αKG to repair DNA.
Previous studies on αKG focused on its role in demethylation of proteins and other molecules. Though the scientific literature pointed towards demethylases as the key enzyme, the scientists focused onTMLHE, an enzyme that initiates the synthesis of carnitine, a molecule often associated with energy metabolism. “Finding TMLHE was the moment I thought, ‘Okay, this is going to be something bigger than what we expected,’” said Katherine Aird, PhD, professor and co-leader of the molecular and cellular oncogenesis program at The Wistar Institute and senior author of the study.
The data indicated that elevated αKG activates TMLHE, which drives carnitine production. Carnitine then carries acetyl groups out of the mitochondria and into the nucleus where they are deposited onto histones. This loosens the DNA-histone complex which allows the cells repair machinery to access and fix DNA damage.
Next the team showed that when TMLHE or carnitine synthesis is blocked, histone acetylation does not occur which prevents the DNA repair machinery from doing its work. In these cases, the cells become significantly more sensitive to DNA-damaging chemotherapies. “The connection between αKG and methylation is well established—that’s what everyone studies,” said Nathaniel Snyder, PhD, associate professor in the Aging + Cardiovascular Discovery Center at Temple University School of Medicine. “What we found is that αKG is also controlling acetylation through a completely separate route, and that route turns out to be essential for DNA repair. That’s a new piece of biology that nobody had described before.”
As part of the study, the scientists tested the effects of mildronate, a carnitine synthesis inhibitor, and cisplatin, a platinum-based DNA-damaging chemotherapy drug. They found that the combination of these treatments reduced the tumor burden in mouse models of ovarian cancer, while neither drug alone produced a significant effect. Additionally, patients with high TMLHE expression in tumor tissue had significantly worse progression-free survival post chemotherapy, and higher serum acetylcarnitine levels at diagnosis correlated with faster disease progression.
That latter finding suggests that it may one day be possible to use a routine blood test for circulating acetylcarnitine to identify patients that are most likely to resist standard platinum-based cancer treatments, and to benefit from a combination therapy.
