Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors

Frank, A. R.; Vandiver, F.; McFadden, D. G.

doi:10.1101/2023.09.30.560315

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bioRxiv · 10.1101/2023.09.30.560315

Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors

Frank, A. R.·Vandiver, F.·McFadden, D. G.

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Abstract

Altered metabolism is a hallmark of cancer; however, it has been difficult to specifically target metabolism in cancer for therapeutic benefit. Cancers with genetically defined defects in metabolic enzymes constitute a subset of cancers where targeting metabolism is potentially accessible. Hurthle cell carcinoma of the thyroid (HTC) tumors frequently harbor deleterious mitochondrial DNA (mtDNA) mutations in subunits of complex I of the mitochondrial electron transport chain (ETC). Previous work has shown that HTC models with deleterious mtDNA mutations exhibit mitochondrial ETC defects that expose lactate dehydrogenase (LDH) as a therapeutic vulnerability. Here, we performed forward genetic screens to identify mechanisms of resistance to small molecule LDH inhibitors. We identified two distinct mechanisms of resistance: upregulation of an LDH isoform and a compound-specific resistance mutation. Using these tools, we demonstrate that the anti-cancer activity of LDH inhibitors in cell line and xenograft models of complex I-mutant HTC is through on-target LDH inhibition.

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Frank, A. R., Vandiver, F., McFadden, D. G.. 2023-09-30. Forward genetic screens identify mechanisms of resistance to small molecule lactate dehydrogenase inhibitors. https://doi.org/10.1101/2023.09.30.560315

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