Recent Progress in Targeting Kinases Involved in the DNA Damage Response for the Treatment of Cancer
TL;DR
The current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours are discussed, as well as the potential benefits of using TPD technology over small-molecule inhibitors.
Abstract
The therapeutic potential of pharmacologically targeting kinases involved in regulating the DNA damage response (DDR) has been investigated for over two decades. Inhibitors of ATM, ATR, CHK1, CHK2 and WEE1 have been developed with the aim of subverting cell cycle checkpoint function in cancer cells, promoting cell death. The DNA repair pathway non-homologous end-joining can also be targeted through DNA-PK inhibition. However, despite extensive preclinical and clinical studies, none of the many candidate inhibitors have yet made it through to clinical approval. Emerging evidence for tumour biomarkers associated with enhanced sensitivity to DDR kinase inhibition may provide a way through this impasse. Clinical testing in appropriately stratified cohorts is now becoming increasingly common, with some promising results. Building on results obtained with small-molecule inhibitors, targeted protein degradation (TPD) utilising proteolysis-targeting chimaeras (PROTACs) or molecular glues for degradation of DDR kinases is a rapidly developing strategy. This review discusses the current ATM, ATR, DNA-PK, CHK1, CHK2 and WEE1 inhibitors that show the most promise as monotherapies and combination treatments in solid tumours, as well as the potential benefits of using TPD technology over small-molecule inhibitors. Established and emerging biomarkers that can be applied to patient selection are also discussed.