Development of a Synthetic Lethal Drug Combination That Targets the Energy Generation Triangle for Liver Cancer Therapy
Technical Report,01 Jun 2016,31 May 2017
University of California, Los Angeles Los Angeles United States
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Metabolic reprogramming in HCC promotes cancer cell survival and growth. This reprograming also suggests possibilities to identify as yet unexplored therapeutic targets. While most normal tissues use HK1 for glycolysis, HK4 is the only HK isoform in hepatocytes. The transition from hepatocyte to HCC is frequently accompanied by a complete switch from HK4 to the highly active HK2 isoform, and increased glycolysis the Warburg effect. HK2 gene deletion in adult mice does not significantly affect normal tissues however, HK2 inhibition in HCC is cytostatic. Our high throughput screen HTC discovered diphenyleneiodonium DPI as a synthetic lethal partner that, in combination with HK2 inhibition, kills HCC cells through its inhibition of mitochondrial complex I. The combination of HK2 inhibition with DPI shifts fatty acid FA metabolism from FA synthesis to FA oxidation FAO in HCC cells to compensate energy loss. Compared to normal liver, HCC up-regulates expression of genes involved in FA biosynthesis and down-regulates expression of genes involved in FAO. Perhexiline PER, a FAO inhibitor in clinical use, sensitizes HCC cells to HK2 inhibitionDPI-induced toxicity. In contrast, the HK2 inhibitionDPIPER combination does not cause significant cytotoxicity in cells from other cancers e.g., breast, lung, colon, suggesting this therapy will be tolerated in vivo. In this study, we developed a triple combination of HK2 inhibition, DPI, and PER to target the energy generation triangle glycolysis, oxidative phosphorylation, and FAO as a translational, effective and safe therapy for HCC.
- Medicine and Medical Research
- Anatomy and Physiology