Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer

The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on immune cells and is highly upregulated in a number of human cancers where it can play a trophic role in tumorigenesis. Activation of this receptor leads to the formation of a non-selective cation channel, which has been associated with several cellular functions mediated by the PI3K/Akt pathway and protein kinases. Due to its broad range of functions, the receptor represents a potential therapeutic target for a number of cancers. This review describes the range of mechanisms associated with P2X7R activation in cancer settings and highlights the potential of targeted inhibition of P2X7R as a therapy. It also describes in detail a number of key P2X7R antagonists currently in pre-clinical and clinical development, including oxidised ATP, Brilliant Blue G (BBG), KN-62, KN-04, A740003, A438079, GSK1482160, CE-224535, JNJ-54175446, JNJ-55308942, and AZ10606120. Lastly, it summarises the in vivo studies and clinical trials associated with the use and development of these P2X7R antagonists in different disease contexts.

Automated summary

The P2X7 receptor is a plasma membrane receptor responsible for sensing extracellular ATP, commonly expressed on immune cells and highly upregulated in various cancers. Activation of this receptor leads to the formation of a non-selective cation channel, playing a potential trophic role in tumorigenesis. The receptor's broad range of functions make it a potential therapeutic target for cancer treatment, with several P2X7 antagonist compounds currently in pre-clinical and clinical development.