Hexokinase 2 Is Targetable for HK1-Negative, HK2-Positive Tumors from a Wide Variety of Tissues of Origin

Abstract

Although absent in most adult tissues, hexokinase 2 (HK2) is expressed in most tumors and contributes to increased glucose consumption and to in vivo tumor ¹⁸F-FDG PET signaling. Methods: Both HK2 knockdown and knockout approaches were used to investigate the role of HK2 in cancer cell proliferation, in vivo xenograft tumor progression, and ¹⁸F-FDG tumor accumulation. BioProfiler Glycolysis analysis monitored cell culture glucose consumption and lactate production; ¹⁸F-FDG PET/CT monitored in vivo tumor glucose accumulation. Cancer Cell Line Encyclopedia data were analyzed for hexokinase 1 (HK1) and HK2 expression. Results: 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-positive/HK2-positive (HK1⁺HK2⁺) cancers, HK2 knockdown in HK1-negative (HK1⁻) HK2⁺ cancer cells results in inhibition of cell proliferation, colony formation, and xenograft tumor progression. Moreover, HK1-knockout (HK1KO)HK2⁺ cancer cells are susceptible to HK2 inhibition, in contrast to their isogenic HK1⁺HK2⁺ parental cells. Conclusion: HK1 and HK2 expression are redundant in tumors; either can provide sufficient aerobic glycolysis for tumor growth, despite a reduction in ¹⁸F-FDG PET signal. Therapeutic HK2 inhibition is likely to be restricted to HK1⁻HK2⁺ tumor subsets, and stratification of tumors that express HK2, but not HK1, should identify tumors treatable with emerging HK2 specific inhibitors.