Scientists identify metabolic target to overcome chemotherapy resistance in ovarian cancer
· Medical Xpressedited by Sadie Harley, reviewed by Andrew Zinin
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Many cancers can be treated by administering DNA-damaging agents, such as platinum-based chemotherapy, because the resulting DNA damage causes the cancer cells to die. A subset of cancers, however, including ovarian cancers, can repair their own DNA. Because such cancers survive despite chemotherapy, ovarian cancer patients whose tumors are DNA repair proficient have historically faced a poor prognosis and commonly recur within six months.
"With these types of ovarian cancers, clinicians throw everything they can at them, and the prognosis is still quite poor," said Katherine Aird, Ph.D., professor and co-leader of the Molecular and Cellular Oncogenesis Program at the Ellen and Ronald Caplan Cancer Center at The Wistar Institute and senior author of the study.
Now, scientists from The Wistar Institute, Temple University, and collaborators across multiple institutions have uncovered a potential target to debilitate the DNA repair in these cancers, and thus overcome treatment resistance.
For the first time, these researchers have shown that a new metabolic process is altered in cancer cells that makes them resistant to DNA-damaging agents. These findings, published in Nature, also point to an existing drug to inhibit this pathway as a promising strategy to break through chemotherapy resistance.
The study centers on alpha-ketoglutarate (αKG), a metabolite which accumulates in DNA repair proficient ovarian tumors. The team first confirmed that αKG was, in fact, playing a key role in the ability of ovarian cancer cells to repair DNA and survive chemotherapy treatment.
To understand how this occurred, Aird's team used a sophisticated CRISPR-based technique to systematically search for the enzyme that enables αKG to repair DNA, thereby protecting cancer cells from chemotherapy.
For nearly two decades, researchers studying αKG in multiple scientific fields focused on its role in driving demethylation, the removal of chemical tags called methyl groups from proteins and other molecules. However, Aird's group instead identified the enzyme TMLHE, which initiates the body's own synthesis of carnitine (a molecule most often associated with energy metabolism).
"Everyone in the field would have told us to look at the demethylases," Aird said. "That's what the literature pointed to. Finding TMLHE was the moment I thought, 'Okay, this is going to be something bigger than what we expected.'"
Working closely with Nathaniel Snyder, Ph.D., associate professor in the Aging + Cardiovascular Discovery Center at Lewis Katz School of Medicine at Temple University, and his laboratory, the collaborative team discovered what was a previously unknown metabolic pathway. Elevated αKG activates TMLHE, which drives carnitine production.
Carnitine in turn acts as a molecular "shuttle," ferrying acetyl groups out of mitochondria and into the cell nucleus, where they are deposited onto histones and act to loosen the DNA-histone complex. Once the DNA-histone complex is loosened, the repair machinery of the cell is able to access and fix damaged chains of DNA.
Importantly, when TMLHE or carnitine synthesis is blocked, histone acetylation does not occur at key sites, and the cancer cells' DNA repair machinery cannot assemble. In turn, the cells become significantly more sensitive to DNA-damaging chemotherapy.
"The connection between αKG and methylation is well established—that's what everyone studies," said Snyder, co-senior author on the paper.
"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."
To advance these findings toward clinical application, the team tested mildronate, a carnitine synthesis inhibitor with a known safety profile in humans. They found that administering mildronate with cisplatin (a platinum-based DNA-damaging chemotherapy drug) reduced tumor burden in mouse models of ovarian cancer, while neither drug alone produced a significant effect.
The researchers also found that patients with high TMLHE expression in tumor tissue had significantly worse progression-free survival after chemotherapy, and that elevated serum acetylcarnitine levels at diagnosis correlated independently with faster disease progression.
The latter finding raises the possibility that a routine blood test for circulating acetylcarnitine could one day identify patients most likely to resist standard platinum-based cancer treatment and to benefit from combination therapy targeting this newly identified pathway.
The implications of the study extend well beyond ovarian cancer. In addition to its involvement across many tumor types, αKG also declines with age and plays important roles in stem cell biology. Because this study demonstrates for the first time that αKG influences histone acetylation—and through it, cells' capacity for DNA repair—scientists have a new way to look at the gene regulation and genomic stability pathways that affect conditions as varied as aging, developmental biology, and a variety of forms of cancer.
This discovery was the product of an extensive multi-institutional collaboration spanning metabolomics, biochemistry, and clinical research. Specialized mass spectrometry capabilities from the laboratory of co-corresponding author Snyder were one of many essential contributions to mapping the metabolic pathway in both cell lines and patient samples.
"This paper required so many different people's energy and expertise," said Apoorva Uboveja, Ph.D., first author and staff scientist in the Aird lab. "It's more fun and more productive to do science in a community. Wistar recognizes and encourages this, and I think the rigorous, interdisciplinary scope of our work reflects it."
Publication details
Apoorva Uboveja et al, αKG-mediated carnitine synthesis drives DNA repair via histone acetylation, Nature (2026). DOI: 10.1038/s41586-026-10584-7
Journal information: Nature
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