View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Pharmacology & Therapeutics 149 (2015) 124–138 Contents lists available at ScienceDirect Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera Associate editor: B. Teicher ATM and ATR as therapeutic targets in cancer Anika Maria Weber, Anderson Joseph Ryan ⁎ Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, The Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK article info abstract Available online 13 December 2014 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 Keywords: ATM and ATR kinases, which induce cell cycle arrest and facilitate DNA repair via their downstream targets. ATM Inhibiting the DDR has become an attractive therapeutic concept in cancer therapy, since (i) resistance to ATR genotoxic therapies has been associated with increased DDR signalling, and (ii) many cancers have defects in cer- DNA damage response tain components of the DDR rendering them highly dependent on the remaining DDR pathways for survival. ATM Synthetic lethality and ATR act as the apical regulators of the response to DNA double strand breaks and replication stress, respec- tively, 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 ratio- nale 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, pro- viding that appropriate biomarkers are developed. © 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). Contents 1. Introduction: the DNA damage response — importantimplicationsfortumourdevelopmentandtreatment.... 124 2. Thephosphatidylinositol-3kinase-relatedkinase(PIKK)family...................... 125 3. Ataxia–telangiectasiamutatedactivationanddownstreamsignalling.................... 126 4. Ataxia–telangiectasiaandRad3relatedactivationanddownstreamsignalling................ 127 5. Interplay between the ataxia–telangiectasia mutated and ataxia–telangiectasia and Rad3 related signalling pathways 127 6. Ataxia–telangiectasiamutatedasatherapeutictarget........................... 127 7. Ataxia–telangiectasiaandRad3relatedasatherapeutictarget....................... 130 8. Syntheticlethalapproaches....................................... 133 9. Biomarkersandpatientselection.................................... 133 10. Conclusion.............................................. 134 Conflictofinterest............................................. 134 Acknowledgments............................................. 134 References................................................. 134 Abbreviations: A-T, ataxia–telangiectasia; ATM, ataxia–telangiectasia mutated; ATR, 1. Introduction: the DNA damage response — – ataxia telangiectasia and Rad3 related; CHK1, checkpoint kinase 1; CHK2, checkpoint important implications for tumour development and treatment kinase 2; DDR, DNA damage response; DNA-PKcs, DNA-dependent protein kinase catalytic subunit; DSB, double-strand break; FAT, FRAP–ATM–TRRAP; FATC, FAT C-terminal; IR, ionising radiation; kd, kinase-dead; MRN, MRE11–RAD50–NBS1; PI3K, phos- Cells are invariably challenged by tens of thousands of lesions inflicted phatidylinositol 3-kinase; PIKK, phosphatidylinositol 3-kinase-related kinase; PARP, on their DNA everyday (Lindhal, 1993). This DNA damage can be caused poly(ADP-ribose)-polymerase; RPA, replication protein A; ssDNA, single-stranded DNA. exogenously by exposure to different types of radiation or genotoxic ⁎ Corresponding author at: Department of Oncology, Cancer Research UK and Medical agents, or endogenously through, for example, base depurination and Research Council Oxford Institute for Radiation Oncology, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7DQ, UK. Tel.: +44 1865 617409. deamination or reactive by-products of cellular metabolism (Lindahl & E-mail address: [email protected] (A.J. Ryan). Barnes, 2000). If unrepaired or aberrantly repaired, such lesions may http://dx.doi.org/10.1016/j.pharmthera.2014.12.001 0163-7258/© 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/3.0/). A.M. Weber, A.J. Ryan / Pharmacology & Therapeutics 149 (2015) 124–138 125 prove lethal to the cell or give rise to deleterious mutations that can approaches. While defects in DDR components may, on the one hand, affect cell viability or induce aberrant cellular behaviour leading to the give cancer cells a growth advantage, allowing them to survive and development of malignancies such as cancer. Because genetic alterations proliferate despite oncogene-induced replication stress and genomic have such a significant potential impact on survival and viability of a cell, instability, they may also drive a reliance of cancer cells on any remaining as well as the organism as a whole, cells have developed a complex DDR pathways in order to survive DNA damage. Targeting of such network of signalling pathways – collectively known as the DNA damage remaining pathways may therefore be selectively toxic to cancer cells response (DDR) – that orchestrates the detection and repair of DNA with mutations in certain DDR genes. The potential of this approach damage with transient cell cycle arrest to ensure maintenance of was first demonstrated in cells harbouring mutations in the breast genomic stability and cell viability (Jackson & Bartek, 2010; Ciccia and ovarian cancer susceptibility genes BRCA1 and BRCA2, which & Elledge, 2011). were shown to be highly sensitive to small molecule inhibitors of The DDR plays an important role in many aspects of cancer. First, poly(ADP-ribose)-polymerase (PARP), a DDR protein that is involved deficiencies in DDR mechanisms have been shown to be contributing in the detection and repair of DNA single strand breaks by base excision factors in many stages of tumour development. Numerous hereditary repair (Bryant et al., 2005; Farmer et al., 2005). The PARP inhibitor cancer predispositions result from mutations in DNA repair genes olaparib has since shown promise for the treatment of BRCA1/2 mutated (Goode et al., 2002; Negrini et al., 2010). For example, women who breast or ovarian cancer in clinical trials (Fong et al., 2009; Audeh et al., carry a defective allele of the BRCA1 or BRCA2 genes, which encode 2010; Tutt et al., 2010). Further studies have demonstrated that inhibition for two proteins centrally involved in the repair of DNA double strand of other components of the DDR machinery can sensitise cancer cells to breaks (DSBs) by homologous recombination, are at much higher risk DNA damaging treatments, including DNA-PKcs (Zhao et al., 2006), of developing breast and ovarian cancers than women in the general ataxia–telangiectasia mutated (ATM) (Rainey et al., 2008; Golding population (Pal et al., 2005; Levy-Lahad & Friedman, 2007). Further- et al., 2012), ataxia–telangiectasia and Rad3 related (ATR) (Fokas et al., more, several studies have demonstrated activation of DDR proteins 2012; Pires et al., 2012; Prevo et al., 2012; Huntoon et al., 2013), or their during early stages of tumourigenesis (Bartkova et al., 2005; Gorgoulis downstream targets CHK1 and CHK2 (Matthews et al., 2007; Blasina et al., 2005). This response has been linked to the induction of replica- et al., 2008; Mitchell et al., 2010; Riesterer et al., 2011). tion stress and DNA damage, caused by abnormal replication due to Here, we focus on the role of ATR and ATM in the DNA damage aberrant oncogene activation (Bartkova et al., 2006; Di Micco et al., response and the current status of development of specific inhibitors 2006). It has been suggested that this activation of DDR pathways may targeting these pathways. We review the studies elucidating the potential limit tumour development in its early stages by acting as a barrier for of these inhibitors to act as radio- and chemosensitisers and discuss the proliferation of aberrant cells (Bartkova et al., 2005; Gorgoulis et al., genetic alterations or cellular phenotypes that suggest which patient 2005), particularly through activation of the tumour suppressor protein subsets may benefit most from these therapies. We also give examples p53 (Halazonetis et al., 2008). Therefore, it is unsurprising that many of synthetic lethal approaches that target these two DDR kinases. malignant tumours show functional loss or deregulation of key proteins involved in the DDR and cell cycle regulation, most notably p53 and 2. The phosphatidylinositol-3 kinase-related kinase (PIKK) family ATM (Cancer Genome Atlas Research Network, 2012a, 2012b, 2012c, 2014; Kandoth et al., 2013), MRE11 (Ottini et al., 2004; Bartkova et al., ATM and ATR are members of the phosphatidylinositol 3-kinase- 2008; Choudhury et al., 2010), BRCA1/2