Targeting Hexokinase 2 May Block Cancer Glucose Metabolism

Glucose metabolism is often accelerated in cancer cells under aerobic conditions to generate increased levels of metabolic intermediates for anabolic processes. The first committed step in glycolysis, the phosphorylation of glucose to yield glucose-6-phosphate, is catalyzed by hexokinases (HK). HK1 is widely and constitutively expressed, whereas HK2 predominates during embryogenesis and is not widely expressed in adult tissues. Given this restricted expression and the observation that HK2 is selectively overexpressed in cancer cells, HK2 may be an attractive target with a wide therapeutic index. Patra and colleagues found that deletion of Hk2 inhibited Ras-induced oncogenic transformation in murine embryonic fibroblasts and profoundly slowed the development of Kras-induced lung cancer and ErbB2-induced breast cancer in vivo despite the presence of HK1, indicating that HK2 is necessary for tumor initiation. Knockdown of HK2 in established lung and breast tumors also significantly inhibited tumor growth and proliferation, also suggesting that HK2 is required for lung and breast cancer maintenance. Consistent with these findings, HK2 was overexpressed in both human lung and breast cancer samples compared with surrounding normal tissue, and the level of HK2 expression increased with tumor stage. Mechanistically, HK2 loss reduced the flow of carbons from glucose into ribonucleotides and was associated with a decrease in DNA synthesis. HK2 inactivation also decreased glycolysis- and glutamine-derived carbon incorporation into anaplerotic intermediates, further pointing to a role for HK2 in the increased metabolic demands of rapidly proliferating cancer cells. Of note, systemic deletion of Hk2 after the establishment of tumors did not induce any obvious adverse physiologic effects while reducing tumor burden, providing preclinical evidence that HK2 inhibition might be an effective and safe therapeutic strategy. These findings thus establish a rationale for the development of selective small-molecule inhibitors of HK2 to exploit the altered metabolism of cancer cells.

Patra KC, Wang Q, Bhaskar PT, Miller L, Wang Z, Wheaton W, et al. Hexokinase 2 is required for tumor initiation and maintenance and its systemic deletion is therapeutic in mouse models of cancer. Cancer Cell 2013;24:213–28.