Targeting pyruvate kinase M2 signaling for development of effective cancer therapy

Warburg effect, a common hallmark of actively proliferating cancer cells, occurs through the reshuffling of glucose metabolism. To meet the high energy demands, cancer cells modulate the metabolism towards less efficient aerobic glycolysis. Pyruvate kinase M2 isoform (PKM2) is one of the major players in such metabolic modulations; it functions as a rate-limiting enzyme of glycolysis. In recent years PKM2 has gained attention due to its role in tumor growth, invasion, and proliferation. PKM2 can be present in two states, the highly active tetrameric and the less active dimeric forms. PKM2 in the dimer state promotes tumorigenesis; it enters the nucleus to regulate gene expression and generate tumor cell energy supply, epithelial-mesenchymal transition (EMT), invasion and metastasis and cell proliferation. PKM2 also goes through various posttranslational modifications to aid cancer cells with survival. The modified PKM2 further interacts with other proteins to perform its pro-cancer effects. Moreover, PKM2 has a role in making cancer cells chemo-resistant, which has alarmed researchers concerned about the kinase's management. In the present chapter, PKM2’s direct and indirect role in cancer has been reported. Various small molecule inhibitors studied at different stages have been illustrated. Inhibitors that have been made through various stages of clinical trials are also discussed. The current chapter explored and highlighted the urgent need for the development of potent PKM2 inhibitors.