posted on 2024-01-25, 16:05authored byAnderson
R. Frank, Florentina Vandiver, David G. McFadden
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 anticancer activity of LDH inhibitors
in cell line and xenograft models of complex I mutant HTC is through
on-target LDH inhibition.