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Ref Type Journal Article
PMID (25512053)
Authors Weber AM, Ryan AJ
Title ATM and ATR as therapeutic targets in cancer.
Journal Vol Issue Date Pages Journal Short Title
Pharmacology & therapeutics 149 2015 May 124-38 Pharmacol Ther
URL
Abstract Text In order to maintain genomic stability, cells have developed sophisticated signalling pathways to enable DNA damage or DNA replication stress to be resolved. Key mediators of this DNA damage response (DDR) are the ATM and ATR kinases, which induce cell cycle arrest and facilitate DNA repair via their downstream targets. Inhibiting the DDR has become an attractive therapeutic concept in cancer therapy, since (i) resistance to genotoxic therapies has been associated with increased DDR signalling, and (ii) many cancers have defects in certain components of the DDR rendering them highly dependent on the remaining DDR pathways for survival. ATM and ATR act as the apical regulators of the response to DNA double strand breaks and replication stress, respectively, with overlapping but non-redundant activities. Highly selective small molecule inhibitors of ATM and ATR are currently in preclinical and clinical development, respectively. Preclinical data have provided a strong rationale for clinical testing of these compounds both in combination with radio- or chemotherapy, and in synthetic lethal approaches to treat tumours with deficiencies in certain DDR components. Whole genome sequencing studies have reported that mutations in DDR genes occur with a high frequency in many common tumour types, suggesting that a synthetic lethal approach with ATM or ATR inhibitors could have widespread utility, providing that appropriate biomarkers are developed.

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Molecular Profile Treatment Approach
ATR over exp ATR Inhibitor
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
ATR NCBI FCTCS|FRP1|MEC1|SCKL|SCKL1 ATR, ATR serine/threonine kinase, is involved in regulation of the DNA damage response and mediation of cell-cycle checkpoints (PMID: 25512053). Loss of function ATR mutations have been identified in melanoma (PMID: 28273450), and inhibition of Atr selectively sensitizes cancerous cells to radiation and chemotherapy (PMID: 23583268, PMID: 31836456, PMID: 29054375). Tumor suppressor
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References