Pre-clinical Profile and Expectations for Pharmacological ATM Inhibition
Weber AM., Ryan AJ.
© 2018, Springer International Publishing AG, part of Springer Nature. The central DNA damage response (DDR) kinase Ataxia-telangiectasia mutated (ATM) has become an attractive target for cancer therapy. Pre-clinical studies have encouraged the further clinical development of ATM inhibitors, both in combination with chemo- or radiotherapy and as a single agent for the treatment of tumours harbouring deficiencies in certain DDR pathways. The challenges for the successful future development of ATM inhibitors for the clinic will be to translate the knowledge of the cellular phenotypes caused by inhibition of ATM function into the identification of the most beneficial combination strategies and treatment schedules, and to identify robust biomarkers for patient selection and assessment of target inhibition. In this chapter we will review the current knowledge of the cellular defects caused by ATM kinase inhibition and the differences from the known defects observed in ATM-deficient cells. We will also discuss some of the pre-clinical data from in vitro studies with pharmacological ATM inhibitors, the (thus far) most promising combinations of ATM inhibitors with genotoxic modalities, potential synthetic lethal approaches and potential biomarkers for patient selection and assessment of target inhibition.