Evidence for a novel, effective approach to targeting carcinoma catabolism exploiting the first-in-class, anti-cancer
Moises O Guardado Rivas1,2,3, Shawn D Stuart1,3, Daniel Thach3
1Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY, United States of America.
Abstract:
Clinical targeting of the altered metabolism of tumor cells has long been considered an attractive hypothetical approach. However, this strategy has yet to perform well clinically. Metabolic redundancy is among the limitations on effectiveness of many approaches, engendering intrinsic single-agent resistance or efficient evolution of such resistance. We describe new studies of the multi-target, tumor-preferential inhibition of the mitochondrial tricarboxylic acid (TCA) cycle by the first-in-class drug CPI-613® (devimistat). By suppressing the TCA hub, indispensable to many metabolic pathways, CPI-613 substantially reduces the effective redundancy of tumor catabolism. This TCA cycle suppression also engenders an apparently homeostatic accelerated, inefficient consumption of nutrient stores in carcinoma cells, eroding some sources of drug resistance. Nonetheless, sufficiently abundant, cell line-specific lipid stores in carcinoma cells are among remaining sources of CPI-613 resistance in vitro and during the in vivo pharmacological drug pulse. Specifically, the fatty acid beta-oxidation step delivers electrons directly to the mitochondrial electron transport system (ETC), by-passing the TCA cycle CPI-613 target and producing drug resistance. Strikingly, tested carcinoma cell lines configure much of this fatty acid flow to initially traverse the peroxisome enroute to additional mitochondrial beta-oxidation. This feature facilitates targeting as clinically practical agents disrupting this flow are available. Two such agents significantly sensitize an otherwise fully CPI-613-resistant carcinoma xenograft in vivo. These and related results are strong empirical support for a potentially general class of strategies for enhanced clinical targeting of carcinoma catabolism.
Insights
New drug CPI-613 targets cancer cell metabolism by inhibiting the tricarboxylic acid (TCA) cycle. This approach overcomes resistance by disrupting nutrient consumption, though lipid metabolism remains a challenge.
Area of Science:
- Oncology
- Cancer Metabolism
- Drug Discovery
Background:
- Targeting tumor cell metabolism is a promising strategy, but clinical success is limited by metabolic redundancy and drug resistance.
- Metabolic redundancy allows cancer cells to utilize alternative pathways, contributing to resistance against single-agent therapies.
Purpose of the Study:
- To investigate the efficacy of CPI-613 (devimistat), a novel inhibitor of the mitochondrial tricarboxylic acid (TCA) cycle, in targeting cancer cell metabolism.
- To explore mechanisms of resistance to CPI-613 and identify strategies to overcome them.
Main Methods:
- Utilized CPI-613 to inhibit the TCA cycle in carcinoma cells, assessing its impact on metabolic redundancy and nutrient consumption.
- Investigated the role of lipid metabolism, specifically fatty acid beta-oxidation and peroxisomal pathways, in mediating resistance to CPI-613.
- Evaluated the combination of CPI-613 with other agents to sensitize resistant cancer xenografts.
Main Results:
- CPI-613 effectively suppressed the TCA cycle, reducing metabolic redundancy and inducing inefficient nutrient consumption in carcinoma cells.
- Lipid stores and fatty acid beta-oxidation, particularly via peroxisomal pathways, were identified as key mechanisms of CPI-613 resistance.
- Combination therapy with agents targeting lipid metabolism significantly sensitized CPI-613-resistant carcinoma xenografts in vivo.
Conclusions:
- Multi-targeted inhibition of the TCA cycle by CPI-613 offers a promising approach to overcome metabolic redundancy in cancer.
- Targeting lipid metabolism pathways, including peroxisomal beta-oxidation, is crucial for enhancing the clinical efficacy of TCA cycle inhibitors.
- These findings support a generalizable strategy for improved clinical targeting of carcinoma metabolism.
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