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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
Published on: December 9, 2015
Forward Genetic Screens Identify Mechanisms of Resistance to Small-Molecule Lactate Dehydrogenase Inhibitors
Anderson R Frank1,2, Florentina Vandiver1,2, David G McFadden1,2,3,4
1Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States.
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 anticancer activity of LDH inhibitors in cell line and xenograft models of complex I mutant HTC is through on-target LDH inhibition.
Insights
Targeting lactate dehydrogenase (LDH) shows promise for treating Hürthle cell carcinoma (HTC) with mitochondrial defects. Researchers identified resistance mechanisms to LDH inhibitors, confirming their on-target anticancer activity in complex I mutant HTC models.
Area of Science:
- Biochemistry
- Oncology
- Genetics
Background:
- Altered cellular metabolism is a key characteristic of cancer, yet targeting metabolic pathways for therapy remains challenging.
- Hürthle cell carcinoma (HTC) of the thyroid frequently presents with mitochondrial DNA (mtDNA) mutations affecting Complex I of the electron transport chain (ETC).
- These ETC defects in HTC create a metabolic vulnerability associated with lactate dehydrogenase (LDH).
Purpose of the Study:
- To identify resistance mechanisms against small-molecule inhibitors targeting LDH in cancer models.
- To validate the therapeutic efficacy of LDH inhibitors in complex I-mutant HTC.
Main Methods:
- Conducted forward genetic screens to discover resistance pathways to LDH inhibitors.
- Utilized cell line and xenograft models of complex I mutant HTC.
- Investigated mechanisms including LDH isoform upregulation and specific resistance mutations.
Main Results:
- Identified two primary mechanisms of resistance to LDH inhibitors: increased LDH isoform expression and specific mutations conferring resistance.
- Demonstrated that the anticancer effects of LDH inhibitors in complex I mutant HTC models are mediated by direct inhibition of LDH.
- Confirmed on-target activity of LDH inhibitors in both cellular and in vivo models.
Conclusions:
- Lactate dehydrogenase (LDH) is a validated therapeutic target in Hürthle cell carcinoma (HTC) with Complex I mitochondrial defects.
- Understanding resistance mechanisms is crucial for developing effective LDH inhibitor-based cancer therapies.
- These findings support the development of LDH inhibitors as a targeted treatment strategy for specific cancer subtypes.
