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

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Abstract

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.

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Prof. Terence J. O’Brien receives research funding from Biogen, UCB Pharma, Eisai Pharma, Anavex Pharmaceuticals, and Zynerba Pharmaceuticals and serves on the scientific advisory boards for UCB Pharma, Eisai Pharmaceuticals, Zynerba Pharmaceuticals, ES Therapeutics, and Seqirus Pharmaceuticals.

Dr. Mastura Monif has received funding for speaker engagements and advisory board service from Merck and Biogen. Her institution receives funding from Merck. Her institution also receives funding from MS Research Australia, Brain Foundation (Australia), Charles and Sylvia Viertel Foundation (Australia), Bethlehem and Griffith Foundation (Australia), and National Health and Medical Research Council (NHMRC).

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  1. Department of Neuroscience, Faculty of Medicine, Nursing and Health Sciences, Central Clinical School, Monash University, Melbourne, VIC, Australia

    Matthew Drill, Nigel C. Jones, Martin Hunn, Terence J. O’Brien & Mastura Monif

  2. Department of Physiology, Melbourne University, Parkville, VIC, Australia

    Matthew Drill & Mastura Monif

  3. Department of Neurology, Alfred Health, Melbourne, VIC, Australia

    Matthew Drill, Terence J. O’Brien & Mastura Monif

  4. Department of Neurosurgery, Alfred Hospital, Melbourne, VIC, Australia

    Martin Hunn

  5. Department of Neurology, Melbourne Health, Parkville, VIC, Australia

    Mastura Monif

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Drill, M., Jones, N.C., Hunn, M. et al. Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer. Purinergic Signalling 17, 215–227 (2021). https://doi.org/10.1007/s11302-021-09776-9

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