Wednesday, February 5, 2025
2/5/2025
We have discovered that elevated levels of the metabolites 2-hydroxyglutarate (2HG), succinate, and fumarate in human cancers suppress homology-dependent repair (HDR) of DNA double-strand breaks (DSBs). 2HG is produced at high levels by the neomorphic activity conferred by isocitrate dehydrogenase-1 and -2 (IDH1/2) mutations in gliomas, sarcomas, cholangiocarcinomas, and acute myeloid leukemia. Elevated levels of fumarate and succinate are found in familial cancer syndromes associated with renal cell carcinomas and paragangliomas/pheochromocytomas, respectively, and are linked to germline mutations in genes encoding the Krebs cycle enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDH). We found that elevated 2HG, fumarate, and succinate suppress HDR by competing with a-ketoglutarate (aKG) to inhibit KDM4B, a histone lysine demethylase that acts on trimethylated histone 3 lysine 9 (H3K9me3). Inhibition of KDM4B results in broad H3K9me3 hypermethylation across the genome, masking the H3K9me3 chromatin signal at the DSB that is essential for recruitment of TIP60 and other factors to initiate HDR. This work was funded by this grant and published in Science Translational Medicine, Nature Genetics, and Nature. Our finding of oncometabolite-induced HDR deficiency identifies defective DNA repair and consequent genomic instability as an unexpected mechanism of carcinogenesis caused by elevated metabolites, and it suggests that IDH1/2, FH, and SDH mutations in human malignancies can be exploited by synthetic lethal targeting with poly-ADP-ribose polymerase inhibitors (PARPi). Our work has therefore provided a novel and previously unsuspected therapeutic strategy for these malignancies that has been rapidly translated into multiple new clinical trials testing the efficacy of PARPi in oncometabolite-producing tumors. This highlights the significance of our work and its relevance to human health. In Aim 1 of this renewal application, we will determine the scope of oncometabolite-induced HDR deficiency in human cancers by testing specific hypotheses regarding metabolism-associated genes that are either mutated or overexpressed in human cancers and assaying their impact on DNA repair. If successful, these efforts will identify additional malignancies with previously unanticipated vulnerability to PARPi that can be rapidly translated into the clinic. In Aim 2, we will discover and optimize new therapeutic strategies for oncometabolite-producing tumors, via mechanistic and pre-clinical studies. We will test for synthetic lethality and synergism, building on an initial small molecule screen, promising preliminary data, and specific mechanistic hypotheses. We will evaluate potential therapies in cell and mouse tumor models to guide new clinical approaches for these tumors. This work will define the landscape of oncometabolite-producing human tumors, accelerate the rational design of new therapeutic strategies for these malignancies, and highlight agents to bring forward for future clinical trials.
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