Ataxia-telangiectasia mutated and ataxia telangiectasia and Rad3-related kinases as therapeutic targets and stratification indicators for prostate cancer

Gulliver, C., Hoffmann, R. and Baillie, G. S. (2022) Ataxia-telangiectasia mutated and ataxia telangiectasia and Rad3-related kinases as therapeutic targets and stratification indicators for prostate cancer. International Journal of Biochemistry and Cell Biology, 147, 106230. (doi: 10.1016/j.biocel.2022.106230) (PMID:35609768)

Abstract

The DNA damage response is an integral part of a cells’ ability to maintain genomic integrity by responding to and ameliorating DNA damage, or initiating cell death for irrepairably damaged cells. This response is often hijacked by cancer cells to evade cell death allowing mutant cells to persist, as well as in the development of treatment resistance to DNA damaging agents such as chemotherapy and radiation. Prostate cancer (PCa) cells often exhibit alterations in DNA damage response genes including ataxia telangiectasia mutated (ATM), correlating with aggressive disease phenotype. The recent success of Poly (ADP-ribose) polymerase (PARP) inhibition has led to several clinically approved PARP inhibitors for the treatment of men with metastatic PCa, however a key limitation is the development of drug resistance and relapse. An alternative approach is selectively targeting ATM and ataxia telangiectasia and Rad3-related (ATR) which, due to their position at the forefront of the DDR, represent attractive pharmacological targets. ATR inhibition has been shown to act synergistically with PARP inhibition and other cancer treatments to enhance anti-tumour activity. ATM-deficiency is a common characteristic of PCa and a synthetic lethal relationship exists between ATM and ATR, with ATR inhibition inducing selective cell death in ATM-deficient PCa cells. The current research highlights the feasibility of therapeutically targeting ATR in ATM-deficient prostate tumours and in combination with other treatments to enhance overall efficacy and reduce therapeutic resistance. ATM also represents an important molecular biomarker to stratify patients into targeted treatment groups and aid prognosis for personalised medicine.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gulliver, Chloe and Hoffmann, Dr Ralf and Baillie, Professor George
• Authors: Gulliver, C., Hoffmann, R., and Baillie, G. S.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Life Sciences
• Journal Name: International Journal of Biochemistry and Cell Biology
• Publisher: Elsevier
• ISSN: 1357-2725
• ISSN (Online): 1878-5875
• Published Online: 21 May 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in International Journal of Biochemistry and Cell Biology 147: 106230
• Publisher Policy: Reproduced under a Creative Commons License