DOCSLIB.ORG

ATM and ATR As Therapeutic Targets in Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
ATM and ATR As Therapeutic Targets in Cancer 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
Load more

Recommended publications
  • DNA Repair and Synthetic Lethality
    Int J Oral Sci (2011) 3:176-179. www.ijos.org.cn REVIEW DNA repair and synthetic lethality Gong-she Guo1, Feng-mei Zhang1, Rui-jie Gao2, Robert Delsite4, Zhi-hui Feng1,3*, Simon N. Powell4* 1School of Public Health, Shandong University, Jinan 250012, China; 2Second People’s Hospital of Weifang, Weifang 261041, China; 3Department of Radiation Oncology, Washington University in St Louis, St Louis MO 63108, USA; 4Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York NY 10065, USA Tumors often have DNA repair defects, suggesting additional inhibition of other DNA repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that DNA repair-defective tumors, in particular homologous recombination (HR), are highly sensitive to DNA-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting DNA repair pathways and other DNA metabolic functions to cause synthetic lethality in HR-defective tumor cells. Keywords: DNA repair; homologous recombination; synthetic lethality; BRCA; Rad52 International Journal of Oral Science (2011) 3: 176-179. doi: 10.4248/IJOS11064 Introduction polymerase (PARP) inhibitors are specifically toxic to homologous recombination (HR)-defective cells [3-4]. Synthetic lethality is defined as a genetic combination Playing a key role in maintaining genetic stability, HR is of mutations in two or more genes that leads to cell a major repair pathway for double-strand breaks (DSBs) death, whereas a mutation in any one of the genes does utilizing undamaged homologous DNA sequence [5-6].
    [Show full text]
  • The Tumor Therapy Landscape of Synthetic Lethality
    ARTICLE https://doi.org/10.1038/s41467-021-21544-2 OPEN The tumor therapy landscape of synthetic lethality Biyu Zhang1,4, Chen Tang1,4, Yanli Yao2,4, Xiaohan Chen1, Chi Zhou 1, Zhiting Wei1, Feiyang Xing1, Lan Chen2, ✉ ✉ Xiang Cai3, Zhiyuan Zhang2, Shuyang Sun 2 & Qi Liu 1 Synthetic lethality is emerging as an important cancer therapeutic paradigm, while the comprehensive selective treatment opportunities for various tumors have not yet been explored. We develop the Synthetic Lethality Knowledge Graph (SLKG), presenting the tumor therapy landscape of synthetic lethality (SL) and synthetic dosage lethality (SDL). SLKG 1234567890():,; integrates the large-scale entity of different tumors, drugs and drug targets by exploring a comprehensive set of SL and SDL pairs. The overall therapy landscape is prioritized to identify the best repurposable drug candidates and drug combinations with literature supports, in vitro pharmacologic evidence or clinical trial records. Finally, cladribine, an FDA-approved multiple sclerosis treatment drug, is selected and identified as a repurposable drug for treating melanoma with CDKN2A mutation by in vitro validation, serving as a demonstrating SLKG utility example for novel tumor therapy discovery. Collectively, SLKG forms the com- putational basis to uncover cancer-specific susceptibilities and therapy strategies based on the principle of synthetic lethality. 1 Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Bioinformatics Department, School of Life Sciences and Technology, Tongji University, Shanghai, China. 2 Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
    [Show full text]
  • Mutational Signatures Are Markers of Drug Sensitivity of Cancer Cells
    bioRxiv preprint doi: https://doi.org/10.1101/2021.05.19.444811; this version posted May 21, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Levatić et al. (2021) bioRxiv Mutational signatures are markers of drug sensitivity of cancer cells Jurica Levatić1, Marina Salvadores1, Francisco Fuster-Tormo1, Fran Supek1,2,* 1 Genome Data Science, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, C/ Baldiri Reixac 10, Barcelona 08028, Spain. 2 Catalan Institution for Advanced Studies (ICREA), Passeig de Lluís Companys, 23, 08010 Barcelona, Spain. * correspondence to: [email protected] Abstract Genomic analyses have revealed mutational signatures that are associated with DNA maintenance gone awry, a common occurrence in tumors. Because cancer therapeutics often target synthesis of DNA building blocks, DNA replication or DNA repair, we hypothesized that mutational signatures would make useful markers of drug sensitivity. We rigorously tested this hypothesis by a global analysis of various drug screening and genetic screening data sets, derived from cancer cell line panels. We introduce a novel computational method that detects mutational signatures in cell lines by stringently adjusting for the confounding germline mutational processes, which are difficult to remove when healthy samples from the same individuals are not available. This revealed many associations between diverse mutational signatures and drug activity in cancer cell lines, which are comparably or more numerous than associations with classical genetic features such as cancer driver mutations or copy number alterations.
    [Show full text]
  • Approaches to Identifying Synthetic Lethal Interactions in Cancer
    YALE JOURNAL OF BIOLOGY AND MEDICINE 88 (2015), pp.145-155. REvIEw Approaches to Identifying Synthetic Lethal Interactions in Cancer Jordan M. Thompson, Quy H. Nguyen, Manpreet Singh, and Olga v. Razorenova* Molecular Biology and Biochemistry Department, University of California Irvine, Irvine, California Targeting synthetic lethal interactions is a promising new therapeutic approach to exploit specific changes that occur within cancer cells. Multiple approaches to investigate these interactions have been developed and successfully implemented, including chemical, siRNA, shRNA, and CRISPR library screens. Genome- wide computational approaches, such as DAISY, also have been successful in predicting synthetic lethal in - teractions from both cancer cell lines and patient samples. Each approach has its advantages and disadvantages that need to be considered depending on the cancer type and its molecular alterations. This review discusses these approaches and examines case studies that highlight their use. INTRODUCTION formed genome [1,2]. Indeed, most of the hallmarks of A major challenge in developing new anti-cancer cancer are associated with changes to the cancer cell’s therapies is to identify compounds that have sufficient genetic makeup in order to enable it to endlessly prolif - therapeutic windows comprised of the concentrations erate [3]. These changes can be exploited to specifically causing tumor regression with minimal normal tissue tox - target and kill cancer cells while sparing normal cells icity. Most cancer therapies suffer from narrow thera - [2,4]. Traditional chemotherapy, including irradiation or peutic windows causing numerous side effects that DNA damaging agents, relies on this principle. Most can - greatly reduce a patient’s quality of life. Further elucida - cer cells have defects in their cell cycle checkpoints tion of the unique differences between cancer and nor - where DNA would normally be repaired before replica - mal tissue allows for the development of targeted tion [5,6].
    [Show full text]
  • RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib
    Published OnlineFirst March 19, 2013; DOI: 10.1158/1535-7163.MCT-12-0950 Molecular Cancer Chemical Therapeutics Therapeutics RAD51C-Deficient Cancer Cells Are Highly Sensitive to the PARP Inhibitor Olaparib Ahrum Min1, Seock-Ah Im1,2, Young-Kwang Yoon1, Sang-Hyun Song1, Hyun-Jin Nam1, Hyung-Seok Hur1, Hwang-Phill Kim1, Kyung-Hun Lee1,2, Sae-Won Han1,2, Do-Youn Oh1,2, Tae-You Kim1,2,4, Mark J. O'Connor5, Woo-Ho Kim1,3, and Yung-Jue Bang1,2 Abstract A PARP inhibitor is a rationally designed targeted therapy for cancers with impaired DNA repair abilities. RAD51C is a paralog of RAD51 that has an important role in the DNA damage response. We found that cell lines sensitive to a novel oral PARP inhibitor, olaparib, had low levels of RAD51C expression using microarray analysis, and we therefore hypothesized that low expression of RAD51C may hamper the DNA repair process, resulting in increased sensitivity to olaparib. Compared with the cells with normal RAD51C expression levels, RAD51C-deficient cancer cells were more sensitive to olaparib, and a higher proportion underwent cell death by inducing G2–M cell-cycle arrest and apoptosis. The restoration of RAD51C in a sensitive cell line caused attenuation of olaparib sensitivity. In contrast, silencingofRAD51Cinaresistant cell line enhanced the sensitivity to olaparib, and the number of RAD51 foci decreased with ablated RAD51C expression. We also found the expression of RAD51C was downregulated in cancer cells due to epigenetic changes and RAD51C expression was low in some gastric cancer tissues. Furthermore, olaparib significantly suppressed RAD51C-deficient tumor growth in a xenograft model.
    [Show full text]
  • Synthetic Lethal Screening in the Mammalian Central Nervous System Identifies Gpx6 As a Modulator of Huntington’S Disease
    Synthetic lethal screening in the mammalian central nervous system identifies Gpx6 as a modulator of Huntington’s disease Reut Shemaa,b, Ruth Kulickea,b, Glenn S. Cowleya, Rachael Steina,b, David E. Roota, and Myriam Heimana,b,c,1 aThe Broad Institute of MIT and Harvard University, Cambridge, MA 02142; bThe Picower Institute for Learning and Memory, Cambridge, MA 02139; and cDepartment of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139 Edited* by David E. Housman, Massachusetts Institute of Technology, Cambridge, MA, and approved November 26, 2014 (received for review September 5, 2014) Huntington’s disease, the most common inherited neurodegener- displayed a unique pattern of gene expression changes associated ative disease, is characterized by a dramatic loss of deep-layer with aging that were consistent across technical replicates and cortical and striatal neurons, as well as morbidity in midlife. Hu- across mice (Datasets S1–S4 and Fig. 1). Only five genes, including man genetic studies led to the identification of the causative gene, two predicted pseudogenes, displayed a statistically significant huntingtin. Recent genomic advances have also led to the identi- altered expression with aging in all cell types (Tnnt2, Gm5425, fication of hundreds of potential interacting partners for hunting- Rnd3, Pisd,andPisd-ps3), indicating that there is not a common tin protein and many hypotheses as to the molecular mechanisms aging program across the cell types studied, but rather that even whereby mutant huntingtin leads to cellular dysfunction and closely related cell types show distinct molecular changes during death. However, the multitude of possible interacting partners normal aging.
    [Show full text]
  • Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma
    cells Review Prognosis, Biology, and Targeting of TP53 Dysregulation in Multiple Myeloma 1, 1, 1 2 3 Erin Flynt y, Kamlesh Bisht y, Vinidhra Sridharan , María Ortiz , Fadi Towfic and Anjan Thakurta 1,* 1 Celgene Corporation, Summit, NJ 07901, USA; efl[email protected] (E.F.); [email protected] (K.B.); [email protected] (V.S.) 2 Celgene Corporation, Celgene Institute for Translational Research Europe, 41092 Sevilla, Spain; [email protected] 3 Celgene Corporation, San Diego, CA 92121, USA; ftowfi[email protected] * Correspondence: [email protected] These authors contributed equally to this work. y Received: 17 December 2019; Accepted: 19 January 2020; Published: 24 January 2020 Abstract: Multiple myeloma (MM) is the second most common hematological cancer and is characterized by genetic features including translocations, chromosomal copy number aberrations, and mutations in key oncogene and tumor suppressor genes. Dysregulation of the tumor suppressor TP53 is important in the pathogenesis of many cancers, including MM. In newly-diagnosed MM patients, TP53 dysregulation occurs in three subsets: monoallelic deletion as part of deletion of chromosome 17p (del17p) (~8%), monoallelic mutations (~6%), and biallelic inactivation (~4%). Del17p is an established high-risk feature in MM and is included in current disease staging criteria. Biallelic inactivation and mutation have also been reported in MM patients but are not yet included in disease staging criteria for high-risk disease. Emerging clinical and genomics data suggest that the biology of high-risk disease is complex, and so far, traditional drug development efforts to target dysregulated TP53 have not been successful. Here we review the TP53 dysregulation literature in cancer and in MM, including the three segments of TP53 dysregulation observed in MM patients.
    [Show full text]
  • Loss-Of-Function Genetic Screens As a Tool to Improve the Diagnosis and Treatment of Cancer
    Oncogene (2009) 28, 4409–4420 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc REVIEW Loss-of-function genetic screens as a tool to improve the diagnosis and treatment of cancer J Mullenders and R Bernards Division of Molecular Carcinogenesis, Centre for Biomedical Genetics and Cancer Genomics Centre, The Netherlands Cancer Institute, Amsterdam, The Netherlands A major impediment to the effective treatment of cancer is is a member of a new class of anticancer drugs, the the molecular heterogeneity of the disease, which is also ‘targeted-therapeutics’ (Sawyers, 2004; Luo et al., 2009b). reflected in an equally diverse pattern of clinical responses These drugs are developed based on knowledge of which to therapy. Currently, only few drugs are available that genes (often kinases) are specifically altered in cancer. can be used safely and effectively to treat cancer. To Therefore, such targeted therapies are highly cancer cell- improve this situation, the development of novel and highly selective and have fewer side effects. Unfortunately, most specific targets for therapy is of utmost importance. cancer types do not have such frequently occurring Possibly even more importantly, we need better tools oncogenic driver event, making it difficult to expand on to predict which patients will respond to specific therapies. the success of this highly effective drug. Consequently, the Such drug response biomarkers will be instrumental to arsenal of targeted cancer therapeutics is small, making individualize the therapy of patients having seemingly the more conventional chemotherapy still the mainstay of similar cancers. In this study, we discuss how RNA treatment in today’s cancer clinic.
    [Show full text]
  • PALB2 Mutations and Breast-Cancer Risk Michele K
    The new england journal of medicine editorials PALB2 Mutations and Breast-Cancer Risk Michele K. Evans, M.D., and Dan L. Longo, M.D. The response to and repair of DNA damage are end. Homologous recombination is also impor- central to our understanding of the causes of tant as the final step in the interstrand cross- breast cancer. DNA damage results from environ- link repair pathway, which is deficient in Fan- mental exposure to genotoxic agents, lifestyle coni’s anemia. BRCA1, BRCA2 (FANCD1), and PALB2 factors, and cellular metabolism. Among the (FANCN), along with FANCJ (BRIP1), facilitate most lethal forms of DNA damage are double- strand invasion to complete interstrand cross- strand breaks. A failure to accurately repair double- link repair.3 strand breaks has catastrophic consequences for In this issue of the Journal, Antoniou and col- the cell, including aneuploidy and genomic in- leagues4 examine the lifetime risk of breast stability. Double-strand breaks may be repaired cancer resulting from germline loss-of-function by homologous recombination or by the error- PALB2 mutations. Their analysis suggests that prone process of nonhomologous end joining. the risk for PALB2 mutation carriers is as high as Homologous recombination is an important fac- the risk borne by BRCA2 mutation carriers. Using tor in the susceptibility to breast cancer, because a modification of the complex-segregation-analy- BRCA1 is directly involved in the repair of dou- sis approach, these authors examined PALB2 ble-strand breaks; it functions as a coordinator truncating, splice, and deletion mutations and of proteins that are important for the response assessed the age-specific risk of breast cancer to DNA damage and has influence over the acti- in families.
    [Show full text]
  • Synthetic Lethality of a Cell-Penetrating Anti-RAD51 Antibody in PTEN-Deficient Melanoma and Glioma Cells
    www.oncotarget.com Oncotarget, 2019, Vol. 10, (No. 13), pp: 1272-1283 Priority Research Paper Synthetic lethality of a cell-penetrating anti-RAD51 antibody in PTEN-deficient melanoma and glioma cells Audrey Turchick1, Yanfeng Liu2, Weixi Zhao2, Inessa Cohen2 and Peter M. Glazer1,2 1 Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 2 Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, USA Correspondence to: Peter M. Glazer, email: [email protected] Keywords: DNA repair; PTEN; RAD51; ATR; 3E10 Received: December 17, 2018 Accepted: January 09, 2019 Published: February 12, 2019 Copyright: Turchick et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT PTEN is a tumor suppressor that is highly mutated in a variety of human cancers. Recent studies have suggested a link between PTEN loss and deficiency in the non- homologous end-joining (NHEJ) pathway of DNA double strand break (DSB) repair. As a means to achieve synthetic lethality in this context, we tested the effect of 3E10, a cell-penetrating autoantibody that inhibits RAD51, a key factor in the alternative pathway of DSB repair, homology dependent repair (HDR). We report here that treatment of PTEN-deficient glioma cells with 3E10 leads to an accumulation of DNA damage causing decreased proliferation and increased cell death compared to isogenic PTEN proficient controls. Similarly, 3E10 was synthetically lethal to a series of PTEN- deficient, patient-derived primary melanoma cell populations.
    [Show full text]
  • Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery
    Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Mengwasser, Kristen Elizabeth. 2018. Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences. Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:41121232 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery A dissertation presented by Kristen Elizabeth Mengwasser to The Division of Medical Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the subject of Biological and Biomedical Sciences Harvard University Cambridge, Massachusetts May 2018 © 2018 Kristen Elizabeth Mengwasser All rights reserved. Dissertation Advisor: Dr. Stephen J Elledge Kristen Elizabeth Mengwasser Genetic Screening Approaches to Cancer Driver Characterization and Synthetic Lethal Target Discovery Abstract Advances in genetic screening technology have expanded the toolkit for systematic perturbation of gene function. While the CRISPR-Cas9 system robustly probes genetic loss-of-function in mammalian cells, a barcoded ORFeome library offers the opportunity to systematically study genetic gain-of-function. We employed these two screening tools for three purposes. First, we performed shRNA and CRISPR-based screens for synthetic lethality with BRCA2 deficiency, in two pairs of BRCA2 isogenic cell lines.
    [Show full text]
  • ATM-Deficient Cancers Provide New Opportunities for Precision Oncology
    cancers Review ATM-Deficient Cancers Provide New Opportunities for Precision Oncology Nicholas R. Jette 1, Mehul Kumar 1, Suraj Radhamani 1, Greydon Arthur 1, Siddhartha Goutam 1, Steven Yip 2, Michael Kolinsky 3, Gareth J. Williams 1, Pinaki Bose 1 and Susan P. Lees-Miller 1,* 1 Department of Biochemistry and Molecular Biology, Robson DNA Science Centre, Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB T2N 1N4, Canada; [email protected] (N.R.J.); [email protected] (M.K.); [email protected] (S.R.); [email protected] (G.A.); [email protected] (S.G.); [email protected] (G.J.W.); [email protected] (P.B.) 2 Tom Baker Cancer Centre, 1331 29 St NW, Calgary, AB T2N 4N2, Canada; [email protected] 3 Cross Cancer Institute, 11560 University Avenue NW, Edmonton, AB T6G 1Z2, Canada; [email protected] * Correspondence: [email protected] Received: 14 February 2020; Accepted: 12 March 2020; Published: 14 March 2020 Abstract: Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.
    [Show full text]