Clues from DNA Repair Mechanisms Could Drive Novel Therapeutic Strategies

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Metabolites from the Krebs cycle were found to suppress the DNA-repair pathway required for the preservation of genomic integrity.
Metabolites from the Krebs cycle were found to suppress the DNA-repair pathway required for the preservation of genomic integrity.

A new study has identified 2 hereditary cancer syndromes as familial DNA repair-deficiency syndromes.1

Hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate dehydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC) both boost the risk for tumors that can be either benign or malignant. Although these tumors are typically removed with surgery, if the tumors have become malignant, there are currently no effective treatment strategies.

“These hereditary syndromes are very interesting, as the same mutation will be present throughout the body, and whether a tumor is malignant or benign largely depends on the tissue of origin,” explained study researcher Brian Shuch, MD, of the department of urology at the Yale University School of Medicine in New Haven, Connecticut. “Even within alterations in the same exact complex — for example, the various genes associated with the SDH conditions — the specific part of the complex [that is] mutated can also influence risk of malignancy.”

According to Dr Shuch, the discovery that these syndromes are DNA repair-deficiency syndromes may serve as an “Achilles heel allowing novel therapeutic strategies.” 

DNA Repair

All normal cells in the human body sustain damage to the DNA from intrinsic processes as well as from exposure to exogenous agents, according to Ranjit Bindra, MD, of the departments of therapeutic radiology and pathology at the Yale University School of Medicine.

“Our cells have evolved elegant systems to repair this damage, which is critical for normal tissue health,” Dr Bindra said. “However, cancers acquire mutations in genes that block or dysregulate DNA repair, which appears to fuel further tumor growth.”

In both HLRCC and SDH PGL/PCC, there are germline loss-of-function mutations in fumarate hydratase and succinate dehydrogenase genes that encode Krebs cycle enzymes. Overproduction  of these enzymes ― fumarate for HLRCC and succinate for SDH PGL/PC— which are part of the process the body uses to turn carbohydrates, fats, and proteins into energy.

The researchers tested tumor samples from patients with these 2 syndromes and found a high frequency of double-stranded breaks in the DNA of patients. The breaks were correlated with the production of high levels of fumarate and succinate. They then found that the high levels of the 2 metabolites suppressed homologous recombination (HR), the process by which cells repair DNA damage.

“By having a blockage in the Krebs cycle, specific intermediates of cellular metabolism are increased. These can poison routine enzymes critical to various cellular functions, including DNA repair pathways [such as] HR to fix double-strand DNA breaks,” Dr Shuch told Cancer Therapy Advisor. “As these cells have an HR defect; further dysregulation of single-strand DNA repair with PARP inhibition leads to cell death.”

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