NEW YORK (GenomeWeb) – Researchers led by a team at Yale University School of Medicine have found that two hereditary cancer syndromes result in the loss of a type of DNA repair that renders tumor cells vulnerable to poly(ADP)-ribose polymerase (PARP) inhibitors, suggesting a new treatment for patients with advanced disease.
In a study published in Nature Genetics today, the researchers, led by senior authors Brian Shuch, Ranjit Bindra, and Peter Glazer, all at Yale, showed that the two syndromes, called hereditary leiomyomatosis and renal cell cancer (HLRCC) and succinate deyhydrogenase-related hereditary paraganglioma and pheochromocytoma (SDH PGL/PCC), lead to the suppression of the homologous recombination DNA repair pathway, which makes the cells sensitive to PARP inhibitors.
HLRCC and SDH PGL/PCC were already known to be caused by mutations in genes encoding the Krebs cycle enzymes fumarate hydratase and succinate dehydrogenase, respectively. As a result, the cells produce elevated levels of fumarate in HLRCC and of succinate in SDH PGL/PCC. However, it had not been well understood how this leads to tumor formation.
Previous studies had shown that gliomas and other cancers with mutations in the IDH enzymes produce a metabolite, 2-hydroxglutarate, that inhibits alpha-ketoglutarate-dependent enzymes, thus deregulating homologous recombination, a DNA repair pathway that cells require to deal with DNA double-strand breaks.
Since fumarate and succinate can also inhibit alpha-KG-dependent enzymes, the researchers thought that an overabundance of those two metabolites might also suppress homologous recombination.
For their study, they profiled primary tumor samples from patients with HLRCC and SDH PGL/PCC and found that they had both high levels of fumarate or succinate and an increased amount of DNA double-strand breaks.
Further studies showed that the metabolites specifically inhibited the enzymes KDM4A and KDM4B, both lysine demethylases, and that this mediated the suppression of homologous recombination.
Next, the researchers hypothesized that because of their DNA repair defect, the tumor cells might be sensitive to DNA damaging agents, including PARP inhibitors, which result in an increase in DNA double strand breaks. In several in vivo studies, they showed that PARP inhibitors indeed inhibited the growth of mouse tumor xenografts deficient in fumarate hydratase or succinate dehydrogenase expression.
The results suggest that patients with the two cancer syndromes may benefit from PARP inhibitors, which have so far been approved by the US Food and Drug Administration for patients with mutations in the BRCA1 or 2 genes.
"Our finding of this unexpected link between metabolism and DNA repair in these cancers is opening up a whole area of research," said Glazer, chair of the Department of Therapeutic Radiology at the Yale Cancer Center, in a statement, "and it gives another example of the importance of DNA repair in cancer formation and cancer therapy."
Shuch and Bindra now plan to test PARP inhibitors in clinical trials for patients with the inherited cancer syndromes, according to the statement.