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Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition
Aaron Boudreau1, Hans E Purkey2, Anna Hitz3
1Discovery Oncology, Genentech, South San Francisco, California, USA.
Abstract:
Metabolic reprogramming in tumors represents a potential therapeutic target. Herein we used shRNA depletion and a novel lactate dehydrogenase (LDHA) inhibitor, GNE-140, to probe the role of LDHA in tumor growth in vitro and in vivo. In MIA PaCa-2 human pancreatic cells, LDHA inhibition rapidly affected global metabolism, although cell death only occurred after 2 d of continuous LDHA inhibition. Pancreatic cell lines that utilize oxidative phosphorylation (OXPHOS) rather than glycolysis were inherently resistant to GNE-140, but could be resensitized to GNE-140 with the OXPHOS inhibitor phenformin. Acquired resistance to GNE-140 was driven by activation of the AMPK-mTOR-S6K signaling pathway, which led to increased OXPHOS, and inhibitors targeting this pathway could prevent resistance. Thus, combining an LDHA inhibitor with compounds targeting the mitochondrial or AMPK-S6K signaling axis may not only broaden the clinical utility of LDHA inhibitors beyond glycolytically dependent tumors but also reduce the emergence of resistance to LDHA inhibition.
Insights
Targeting lactate dehydrogenase A (LDHA) impacts tumor metabolism. Combining LDHA inhibitors with other drugs may overcome resistance and broaden therapeutic applications for cancer.
Area of Science:
- Oncology
- Cancer Metabolism
- Biochemistry
Background:
- Metabolic reprogramming is a hallmark of cancer, offering potential therapeutic targets.
- Lactate dehydrogenase A (LDHA) plays a key role in tumor metabolism, particularly in glycolysis.
Purpose of the Study:
- To investigate the role of LDHA in tumor growth using genetic and pharmacological inhibition.
- To identify resistance mechanisms to LDHA inhibition and explore strategies to overcome them.
Main Methods:
- Utilized shRNA depletion and a novel LDHA inhibitor (GNE-140) in vitro and in vivo.
- Assessed metabolic changes and cell viability in pancreatic cancer cell lines.
- Investigated resistance mechanisms involving oxidative phosphorylation (OXPHOS) and the AMPK-mTOR-S6K pathway.
Main Results:
- LDHA inhibition rapidly altered metabolism in MIA PaCa-2 cells, with cell death observed after 2 days.
- Glycolysis-independent cell lines showed resistance to GNE-140 but could be resensitized with phenformin (OXPHOS inhibitor).
- Acquired resistance was linked to AMPK-mTOR-S6K pathway activation, leading to increased OXPHOS.
Conclusions:
- Combining LDHA inhibitors with OXPHOS or AMPK-S6K pathway inhibitors can broaden their clinical utility.
- This combination strategy may be effective against glycolytically dependent and independent tumors.
- Targeting resistance pathways can prevent the emergence of resistance to LDHA inhibition.
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