Hexokinase 2 is targetable for HK1 negative, HK2 positive tumors from a wide variety of tissues of origin

Although absent in most adult tissues, hexokinase 2 (HK2) is expressed in a majority of tumors and contributes to increased glucose consumption and to in vivo tumor F-FDG PET signaling. Both HK2 knockdown and knockout approaches were used to investigate the role of HK2 in cancer cell proliferation, in vivo xenograft tumor progression and F-FDG tumor accumulation. BioProfiler analysis monitored cell culture glucose consumption and lactate production; F-FDG PET/CT monitored in vivo tumor glucose accumulation. Cancer Cell Line Encyclopedia data were analyzed for HK1 and HK2 expression. Neither cell proliferation in culture nor xenograft tumor progression are inhibited by HK2 knockdown or knockout in cancer cells that express HK1 and HK2. However, cancer subsets from a variety of tissues of origin express only HK2, but not HK1. In contrast to HK1+HK2+ cancers, HK2 knockdown in HK1-HK2+ cancer cells results in inhibition of cell proliferation, colony formation and xenograft tumor progression. Moreover, HK1KOHK2+ cancer cells are susceptible to HK2 inhibition, in contrast to their isogenic HK1+HK2+ parental cells. HK1 and HK2 expression are redundant in tumors; either can provide sufficient aerobic glycolysis for tumor growth; despite a reduction in F-FDG PET signal. Therapeutic HK2 inhibition is likely to be restricted to HK1-HK2+ tumor subsets, but stratification of tumors that express HK2, but not HK1, should identify tumors treatable with emerging HK2 specific inhibitors.