Abstract B37: Targeting the energy generation triangle to achieve synthetic lethality for treatment of hepatocellular carcinoma

In this study, we developed a synthetic lethal drug combination to treat HCC through the inhibition of the energy generation triangle. Most cancers, including HCC, increase glycolysis (the Warburg effect) to ensure sufficient supplies of energy (ATP), reducing equivalents (NADPH), and biochemical building blocks for cell growth and proliferation. Unlike most tumors, which express both hexokinase 1 (HK1) and HK2, many HCC tumors express only HK2, whereas normal hepatocytes only express HK4. We investigated the role of HK2 in HCC using a doxycycline (DOX)-inducible shRNA knockdown system. The HK4-to-HK2 isoform switch during hepatocarcinogenesis results in high sensitivity to HK2 silencing-induced glycolysis inhibition and cytostasis in HCC cells, in contrast to cancer cells expressing both HK1 and HK2. We performed a high throughput screen (HTS) of 3,205 drug-like small molecules and 119 FDA-approved oncology drugs to identify synthetic lethal partners of HK2 knockdown, using the CellTiter-Glo assay for primary HTS and confirmed with the alamarBlue assay. Diphenyleneiodonium (DPI), a mitochondrial complex-I inhibitor, is the best compound in our HTS that shows synthetic lethality in combination with HK2 silencing/inhibition in HCC cells that express only HK2. Cell proliferation was measured by the MTT assay and cell counting. Cytotoxicity was measured using Trypan blue to distinguish live and dead cells. HK2 activity in xenograft tumors was monitored non-invasively using 18F-f...
Source: Molecular Cancer Therapeutics - Category: Cancer & Oncology Authors: Tags: Chemical Biology: Poster Presentations - Proffered Abstracts Source Type: research