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

  • bioRxiv. 2023 Sep 30:2023.09.30.560315. doi: 10.1101/2023.09.30.560315.
Anderson R Frank  1  2 ,  Florentina Vandiver  1  2 ,  David G McFadden  1  2  3  4  5
Affiliations
  • 1. Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 2. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 3. Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 4. Program in Molecular Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 5. Lead contact.
PMID: 37808702 DOI: 10.1101/2023.09.30.560315
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. Hürthle 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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