Harnessing the complexity of DNA-damage response pathways to improve cancer treatment outcomes

The DNA-damage response (DDR) pathways consist of interconnected components that respond to DNA damage to allow repair and promote cell survival. The DNA repair pathways and downstream cellular responses have diverged in cancer cells compared with normal cells because of genetic alterations that underlie drug resistance, disabled repair and resistance to apoptosis. Consequently, abrogating DDR pathways represents an important mechanism for enhancing the therapeutic index of DNA-damaging anticancer agents. In this review, we discuss the DDR pathways that determine antitumor effects of DNA-damaging agents with a specific focus on treatment outcomes in tumors carrying a defective p53 pathway. Finely tuned survival and death pathways govern the cellular responses downstream of the cytotoxic insults inherent in anticancer treatment. The significance and relative contributions of cellular responses including apoptosis, mitotic catastrophe and senescence are discussed in relation to the web of molecular interactions that affect such outcomes. We propose that promising combinations of DNA-damaging anticancer treatments with DDR-pathway inhibition would be further enhanced by activating downstream apoptotic pathways. The proposed rationale ensures that actual cell death is the preferred outcome of cancer treatment instead of other responses, including reversible cell cycle arrest, autophagy or senescence. Finally, to better measure the contribution of different cellular responses to anticancer treatments, multiplex in vivo assessments of therapy-induced response pathways such as cell death, senescence and mitotic catastrophe is desirable rather than the current reliance on the measurement of a single response pathway such as apoptosis.

[1]  Benjamin Thierry,et al.  Immunotargeting of Functional Nanoparticles for MRI detection of Apoptotic Tumor Cells , 2009, Advanced materials.

[2]  A. Kimchi,et al.  Life and death partners: apoptosis, autophagy and the cross-talk between them , 2009, Cell Death and Differentiation.

[3]  Stephen S. Taylor,et al.  Cancer cells display profound intra- and interline variation following prolonged exposure to antimitotic drugs. , 2008, Cancer cell.

[4]  R A Knight,et al.  Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009 , 2005, Cell Death and Differentiation.

[5]  R. Kim,et al.  Recent advances in understanding the cell death pathways activated by anticancer therapy , 2005, Cancer.

[6]  N. Sato,et al.  Radiation-induced centrosome overduplication and multiple mitotic spindles in human tumor cells. , 2000, Experimental cell research.

[7]  D. Patt,et al.  Efficacy of BSI-201, a poly (ADP-ribose) polymerase-1 (PARP1) inhibitor, in combination with gemcitabine/carboplatin (G/C) in patients with metastatic triple-negative breast cancer (TNBC): Results of a randomized phase II trial. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[8]  M. Duffy,et al.  Survivin: a promising tumor biomarker. , 2007, Cancer letters.

[9]  R. Hruban,et al.  p53-independent expression of the cyclin-dependent kinase inhibitor p21 in pancreatic carcinoma. , 1995, The American journal of pathology.

[10]  Y. Shukla,et al.  Role of senescence and mitotic catastrophe in cancer therapy , 2010, Cell Division.

[11]  P. Stambrook,et al.  Restoration of an absent G1 arrest and protection from apoptosis in embryonic stem cells after ionizing radiation. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Shokat,et al.  Effect of combined DNA repair inhibition and G2 checkpoint inhibition on cell cycle progression after DNA damage , 2006, Molecular Cancer Therapeutics.

[13]  Soyoung Lee,et al.  A Senescence Program Controlled by p53 and p16INK4a Contributes to the Outcome of Cancer Therapy , 2002, Cell.

[14]  A. Sancar,et al.  Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. , 2004, Annual review of biochemistry.

[15]  N. Curtin,et al.  Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. , 2006, Cancer research.

[16]  Robert Almassy,et al.  Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. , 2004, Journal of the National Cancer Institute.

[17]  M. Bataller,et al.  Cell death pathways in response to antitumor therapy. , 2009, Tumori.

[18]  I. Roninson,et al.  If not apoptosis, then what? Treatment-induced senescence and mitotic catastrophe in tumor cells. , 2001, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[19]  A. Villunger,et al.  BH3-only proteins in cell death initiation, malignant disease and anticancer therapy , 2006, Cell Death and Differentiation.

[20]  S. Kern,et al.  Absence of specific cell killing of the BRCA2-deficient human cancer cell line CAPAN1 by poly(ADP-ribose) polymerase inhibition , 2005, Cancer biology & therapy.

[21]  A. Lehmann DNA Damage Tolerance and Translesion Synthesis (Chapter 10) , 2009 .

[22]  P. O'Connor,et al.  Breaching the DNA damage checkpoint via PF-00477736, a novel small-molecule inhibitor of checkpoint kinase 1 , 2008, Molecular Cancer Therapeutics.

[23]  G. Wilson,et al.  Apoptosis Genes and Resistance to Cancer Therapy: What Does the Experimental and Clinical Data Tell Us? , 2003, Cancer biology & therapy.

[24]  B. Zhivotovsky,et al.  Death through a tragedy: mitotic catastrophe , 2008, Cell Death and Differentiation.

[25]  Jiri Bartek,et al.  Targeting the checkpoint kinases: chemosensitization versus chemoprotection , 2004, Nature Reviews Cancer.

[26]  M. Brown,et al.  In vivo Targeting of Dead Tumor Cells in a Murine Tumor Model Using a Monoclonal Antibody Specific for the La Autoantigen , 2007, Clinical Cancer Research.

[27]  P. Keng,et al.  9-1-1 Complex Involvement in DNA Repair: Evidence that DNA Damage Detection Machinery Participates in DNA Repair , 2005, Cell cycle.

[28]  R. Abraham Cell cycle checkpoint signaling through the ATM and ATR kinases. , 2001, Genes & development.

[29]  S. Tanuma,et al.  Checkpoint kinase 1 is cleaved in a caspase-dependent pathway during genotoxic stress-induced apoptosis. , 2007, Biological & pharmaceutical bulletin.

[30]  J. Campisi Cellular Senescence and Its Effects on Carcinogenesis , 2008 .

[31]  I. Ziv,et al.  Monitoring of Chemotherapy-Induced Cell Death in Melanoma Tumors by N,N′-Didansyl-L-cystine , 2007, Technology in cancer research & treatment.

[32]  J. Christensen,et al.  PF-00477736 Mediates Checkpoint Kinase 1 Signaling Pathway and Potentiates Docetaxel-Induced Efficacy in Xenografts , 2009, Clinical Cancer Research.

[33]  M. Kelley,et al.  DNA repair proteins as molecular targets for cancer therapeutics. , 2008, Anti-cancer agents in medicinal chemistry.

[34]  D. Guernsey,et al.  Stem cells, senescence, neosis and self-renewal in cancer , 2006, Cancer Cell International.

[35]  S. Powell,et al.  Targeting the DNA damage response for cancer therapy. , 2009, DNA repair.

[36]  S. Horwitz,et al.  Mechanisms of Taxol-induced cell death are concentration dependent. , 1998, Cancer research.

[37]  J. Shay,et al.  BRAFE600-associated senescence-like cell cycle arrest of human naevi , 2005, Nature.

[38]  S. Baird,et al.  IAP-targeted therapies for cancer , 2008, Oncogene.

[39]  Szu-Yu Chen,et al.  Escape from therapy-induced accelerated cellular senescence in p53-null lung cancer cells and in human lung cancers. , 2005, Cancer research.

[40]  D. Hallahan,et al.  DNA-dependent protein kinase is a molecular target for the development of noncytotoxic radiation-sensitizing drugs. , 2005, Cancer research.

[41]  M. Sivasubramaniam,et al.  Ku70 Corrupts DNA Repair in the Absence of the Fanconi Anemia Pathway , 2010, Science.

[42]  M. Bataller,et al.  Mechanisms of drug-induced mitotic catastrophe in cancer cells. , 2010, Current pharmaceutical design.

[43]  A. Ashworth,et al.  BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of poly (ADP-ribose) polymerase: An issue of potency , 2005, Cancer biology & therapy.

[44]  George Iliakis,et al.  Backup pathways of NHEJ in cells of higher eukaryotes: cell cycle dependence. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[45]  A. Lau,et al.  Selective Inhibition of BRCA2-Deficient Mammary Tumor Cell Growth by AZD2281 and Cisplatin , 2008, Clinical Cancer Research.

[46]  M. Tilby,et al.  A novel DNA-dependent protein kinase inhibitor, NU7026, potentiates the cytotoxicity of topoisomerase II poisons used in the treatment of leukemia. , 2004, Blood.

[47]  Jonathan Maybaum,et al.  Gemcitabine sensitization by checkpoint kinase 1 inhibition correlates with inhibition of a Rad51 DNA damage response in pancreatic cancer cells , 2009, Molecular Cancer Therapeutics.

[48]  R. Prathapan,et al.  Prediction of radiosensitivity of oral cancers by serial cytological assay of nuclear changes. , 1998, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[49]  Jason A. Koutcher,et al.  Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis , 2005, Nature.

[50]  John C Reed,et al.  Drug Insight: cancer therapy strategies based on restoration of endogenous cell death mechanisms , 2006, Nature Clinical Practice Oncology.

[51]  M. Meuth,et al.  ATR and Chk1 Suppress a Caspase-3–Dependent Apoptotic Response Following DNA Replication Stress , 2009, PLoS genetics.

[52]  Marco Foiani,et al.  Regulation of DNA repair throughout the cell cycle , 2008, Nature Reviews Molecular Cell Biology.

[53]  N. Curtin,et al.  Novel Poly(ADP-ribose) Polymerase-1 Inhibitor, AG14361, Restores Sensitivity to Temozolomide in Mismatch Repair-Deficient Cells , 2004, Clinical Cancer Research.

[54]  Wei Zhang,et al.  Centrosome-associated regulators of the G2/M checkpoint as targets for cancer therapy , 2009, Molecular Cancer.

[55]  P. Calsou,et al.  Involvement of Poly(ADP-ribose) Polymerase-1 and XRCC1/DNA Ligase III in an Alternative Route for DNA Double-strand Breaks Rejoining* , 2004, Journal of Biological Chemistry.

[56]  N. Curtin,et al.  Discovery of potent chromen-4-one inhibitors of the DNA-dependent protein kinase (DNA-PK) using a small-molecule library approach. , 2005, Journal of medicinal chemistry.

[57]  I. Hardcastle,et al.  Selective benzopyranone and pyrimido[2,1-a]isoquinolin-4-one inhibitors of DNA-dependent protein kinase: synthesis, structure-activity studies, and radiosensitization of a human tumor cell line in vitro. , 2005, Journal of medicinal chemistry.

[58]  J. Nickoloff,et al.  Regulation of DNA double-strand break repair pathway choice , 2008, Cell Research.

[59]  M. Brown,et al.  APOMAB®, a La-Specific Monoclonal Antibody, Detects the Apoptotic Tumor Response to Life-Prolonging and DNA-Damaging Chemotherapy , 2009, PloS one.

[60]  M. Ljungman Dial 9-1-1 for p53: mechanisms of p53 activation by cellular stress. , 2000, Neoplasia.

[61]  M. Verheij,et al.  Prognostic significance of 99mTc Hynic-rh-annexin V scintigraphy during platinum-based chemotherapy in advanced lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[62]  D. Green,et al.  Chk1 Suppresses a Caspase-2 Apoptotic Response to DNA Damage that Bypasses p53, Bcl-2, and Caspase-3 , 2008, Cell.

[63]  B. Zhivotovsky,et al.  DNA damage induces two distinct modes of cell death in ovarian carcinomas , 2008, Cell Death and Differentiation.

[64]  A. Ashworth,et al.  Targeted therapy for cancer using PARP inhibitors. , 2008, Current opinion in pharmacology.

[65]  B. Reina-San-Martin,et al.  Parp1 facilitates alternative NHEJ, whereas Parp2 suppresses IgH/c-myc translocations during immunoglobulin class switch recombination , 2009, The Journal of experimental medicine.

[66]  George Iliakis,et al.  PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways , 2006, Nucleic acids research.

[67]  L. Walensky BCL-2 in the crosshairs: tipping the balance of life and death , 2006, Cell Death and Differentiation.

[68]  B. Orelli,et al.  RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors. , 2007, Cancer research.

[69]  N. Curtin,et al.  Poly(ADP-Ribose) polymerase-1 and DNA-dependent protein kinase have equivalent roles in double strand break repair following ionizing radiation. , 2009, International journal of radiation oncology, biology, physics.

[70]  Z. Tao,et al.  Chk1 inhibitors for novel cancer treatment. , 2006, Anti-cancer agents in medicinal chemistry.

[71]  Oscar Fernandez-Capetillo,et al.  p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint , 2009, Molecular and Cellular Biology.

[72]  D. Boothman,et al.  New tricks for old drugs: the anticarcinogenic potential of DNA repair inhibitors , 2006, Journal of Molecular Histology.

[73]  I. Roninson,et al.  Role of p53 and p21waf1/cip1 in senescence-like terminal proliferation arrest induced in human tumor cells by chemotherapeutic drugs , 1999, Oncogene.

[74]  Laurence H. Hurley,et al.  DNA and its associated processes as targets for cancer therapy , 2002, Nature Reviews Cancer.

[75]  H. Stein,et al.  Oncogene-induced senescence as an initial barrier in lymphoma development , 2005, Nature.

[76]  N. Curtin,et al.  Identification of potent nontoxic poly(ADP-Ribose) polymerase-1 inhibitors: chemopotentiation and pharmacological studies. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[77]  L. Mir,et al.  Bleomycin, an apoptosis-mimetic drug that induces two types of cell death depending on the number of molecules internalized. , 1993, Cancer research.

[78]  J. Bartek,et al.  Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent Phosphorylation of Chk1 on Ser-317 in Response to Ionizing Radiation* , 2003, The Journal of Biological Chemistry.

[79]  George Iliakis,et al.  Repair of radiation induced DNA double strand breaks by backup NHEJ is enhanced in G2. , 2008, DNA repair.

[80]  R. Bernards,et al.  Distinct Initiation and Maintenance Mechanisms Cooperate to Induce G1 Cell Cycle Arrest in Response to DNA Damage , 2000, Cell.

[81]  Alan Ashworth,et al.  Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. , 2006, Cancer research.

[82]  K. Helin,et al.  Deregulated E2F Activity Induces Hyperplasia and Senescence-Like Features in the Mouse Pituitary Gland , 2005, Molecular and Cellular Biology.

[83]  B. Wouters,et al.  Apoptosis: mediator or mode of cell killing by anticancer agents? , 2001, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[84]  B. Ruggeri,et al.  Chemopotentiation of temozolomide, irinotecan, and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. , 2003, Molecular cancer therapeutics.

[85]  S. Maddika,et al.  Cell survival, cell death and cell cycle pathways are interconnected: implications for cancer therapy. , 2007, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[86]  Michael B Yaffe,et al.  p53-deficient cells rely on ATM- and ATR-mediated checkpoint signaling through the p38MAPK/MK2 pathway for survival after DNA damage. , 2007, Cancer cell.

[87]  A. Howlett,et al.  SU11752 inhibits the DNA-dependent protein kinase and DNA double-strand break repair resulting in ionizing radiation sensitization , 2004, Oncogene.

[88]  A. Pettitt,et al.  DNA-Dependent Protein Kinase Is a Therapeutic Target and an Indicator of Poor Prognosis in B-Cell Chronic Lymphocytic Leukemia , 2008, Clinical Cancer Research.

[89]  R. Weissleder,et al.  In vivo imaging of beta-galactosidase activity using far red fluorescent switch. , 2004, Cancer research.

[90]  C. Schmitt,et al.  Exploiting Drug-Induced Senescence in Transgenic Mouse Models , 2008 .

[91]  S. Elledge,et al.  The DNA damage response: putting checkpoints in perspective , 2000, Nature.

[92]  P. Jeggo,et al.  ATR‐dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling , 2006, The EMBO journal.

[93]  R. Lockshin,et al.  Historical Studies of Various Forms of Cell Death , 2008 .

[94]  C. Streffer,et al.  Predictive assays for the therapy of rectum carcinoma. , 1986, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[95]  T. Helleday,et al.  Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair , 2006, Nucleic acids research.

[96]  E. Bahassi,et al.  The Plk3-Cdc25 circuit , 2005, Oncogene.

[97]  D. Bredesen,et al.  Toward a Mechanistic Taxonomy for Programmed Cell Death Pathways , 2008 .

[98]  D. Altieri Validating survivin as a cancer therapeutic target , 2003, Nature Reviews Cancer.

[99]  K. Khanna,et al.  DNA double-strand breaks: signaling, repair and the cancer connection , 2001, Nature Genetics.

[100]  C. Streffer,et al.  Changes in S-phase fraction and micronucleus frequency as prognostic factors in radiotherapy of cervical carcinoma. , 1995, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[101]  H. Lieberman DNA damage repair and response proteins as targets for cancer therapy. , 2008, Current medicinal chemistry.

[102]  M. Meuth,et al.  Chk1 and p21 cooperate to prevent apoptosis during DNA replication fork stress. , 2005, Molecular biology of the cell.

[103]  E. Bernhard,et al.  How does radiation kill cells? , 1999, Current opinion in chemical biology.

[104]  J. Low,et al.  Current Development of Clinical Inhibitors of Poly(ADP-Ribose) Polymerase in Oncology , 2007, Clinical Cancer Research.

[105]  M. Wideł,et al.  The increment of micronucleus frequency in cervical carcinoma during irradiation in vivo and its prognostic value for tumour radiocurability , 1999, British Journal of Cancer.

[106]  C. Britten,et al.  G2 checkpoint abrogation and checkpoint kinase-1 targeting in the treatment of cancer , 2008, British Journal of Cancer.

[107]  John Calvin Reed Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities , 2006, Cell Death and Differentiation.

[108]  E. Bahassi,et al.  Priming phosphorylation of Chk2 by polo-like kinase 3 (Plk3) mediates its full activation by ATM and a downstream checkpoint in response to DNA damage. , 2006, Mutation research.

[109]  A. Strasser,et al.  Unleashing the power of inhibitors of oncogenic kinases through BH3 mimetics , 2009, Nature Reviews Cancer.

[110]  M. Shabbout,et al.  BH3 peptidomimetics potently activate apoptosis and demonstrate single agent efficacy in neuroblastoma , 2006, Oncogene.

[111]  Thomas Helleday,et al.  Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase , 2007, Nature.

[112]  E. Yang,et al.  BCL2 family in DNA damage and cell cycle control , 2006, Cell Death and Differentiation.

[113]  K. Roemer,et al.  p21 Waf1/Cip1 can protect human colon carcinoma cells against p53-dependent and p53-independent apoptosis induced by natural chemopreventive and therapeutic agents , 2001, Oncogene.

[114]  S. Joel,et al.  DNA damage is able to induce senescence in tumor cells in vitro and in vivo. , 2002, Cancer research.

[115]  B. Wouters,et al.  Apoptosis, p53, and tumor cell sensitivity to anticancer agents. , 1999, Cancer research.

[116]  Xiao-dan Liu,et al.  Inactivation of DNA-dependent protein kinase leads to spindle disruption and mitotic catastrophe with attenuated checkpoint protein 2 Phosphorylation in response to DNA damage. , 2010, Cancer research.

[117]  R. Korneluk,et al.  The inhibitors of apoptosis (IAPs) as cancer targets , 2007, Apoptosis.

[118]  A. D’Andrea,et al.  DNA repair pathways in clinical practice: lessons from pediatric cancer susceptibility syndromes. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[119]  D. Baltimore,et al.  ATR disruption leads to chromosomal fragmentation and early embryonic lethality. , 2000, Genes & development.

[120]  J Wade Harper,et al.  The DNA damage response: ten years after. , 2007, Molecular cell.

[121]  M. Meuth,et al.  Apoptosis induced by replication inhibitors in Chk1-depleted cells is dependent upon the helicase cofactor Cdc45 , 2008, Cell Death and Differentiation.

[122]  Huichen Wang,et al.  DNA ligase III as a candidate component of backup pathways of nonhomologous end joining. , 2005, Cancer research.

[123]  D. Parry,et al.  Chk1 is Essential for Tumor Cell Viability Following Activation of the Replication Checkpoint , 2005, Cell cycle.

[124]  D. Adams,et al.  53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers , 2010, Nature Structural &Molecular Biology.

[125]  W. Plunkett,et al.  H2AX phosphorylation marks gemcitabine-induced stalled replication forks and their collapse upon S-phase checkpoint abrogation , 2007, Molecular Cancer Therapeutics.

[126]  E. Plummer Inhibition of poly(ADP-ribose) polymerase in cancer. , 2006, Current opinion in pharmacology.

[127]  Erik Meulmeester,et al.  p53: a guide to apoptosis. , 2008, Current cancer drug targets.

[128]  J. Masson,et al.  Targeting poly(ADP-ribosyl)ation: a promising approach in cancer therapy. , 2005, Trends in molecular medicine.

[129]  Stephen Fox,et al.  Subtypes of familial breast tumours revealed by expression and copy number profiling , 2010, Breast Cancer Research and Treatment.

[130]  Z. Hořejší,et al.  Preventing nonhomologous end joining suppresses DNA repair defects of Fanconi anemia. , 2010, Molecular cell.

[131]  S. Cory,et al.  The Bcl-2 apoptotic switch in cancer development and therapy , 2007, Oncogene.

[132]  B. F. Taylor,et al.  p53 Suppression of Arsenite-Induced Mitotic Catastrophe Is Mediated by p21CIP1/WAF1 , 2006, Journal of Pharmacology and Experimental Therapeutics.

[133]  R. Lock,et al.  Dual modes of death induced by etoposide in human epithelial tumor cells allow Bcl-2 to inhibit apoptosis without affecting clonogenic survival. , 1996, Cancer research.

[134]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[135]  T. Ried,et al.  Atm deficiency results in severe meiotic disruption as early as leptonema of prophase I. , 1998, Development.

[136]  K. Yamashita,et al.  Cleavage-mediated Activation of Chk1 during Apoptosis* , 2008, Journal of Biological Chemistry.

[137]  I. Roninson,et al.  Tumor senescence as a determinant of drug response in vivo. , 2002, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[138]  M. O’Connor,et al.  Targeted cancer therapies based on the inhibition of DNA strand break repair , 2007, Oncogene.

[139]  Zhan Xiao,et al.  Selective Chk1 inhibitors differentially sensitize p53‐deficient cancer cells to cancer therapeutics , 2006, International journal of cancer.

[140]  E. Friedberg How nucleotide excision repair protects against cancer , 2001, Nature Reviews Cancer.

[141]  M. Tilby,et al.  Sensitization of breast carcinoma cells to ionizing radiation by small molecule inhibitors of DNA-dependent protein kinase and ataxia telangiectsia mutated. , 2005, Biochemical pharmacology.

[142]  R. Mason,et al.  19F‐NMR detection of lacZ gene expression via the enzymic hydrolysis of 2‐fluoro‐4‐nitrophenyl β‐D‐galactopyranoside in vivo in PC3 prostate tumor xenografts in the mouse 1 , 2007, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[143]  Jiri Bartek,et al.  ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks , 2006, Nature Cell Biology.

[144]  S. Boulton DNA repair: Decision at the break point , 2010, Nature.

[145]  E. Kass,et al.  Loss of 53BP1 is a gain for BRCA1 mutant cells. , 2010, Cancer cell.

[146]  G. Iliakis,et al.  Premature chromosome condensation reveals DNA-PK independent pathways of chromosome break repair. , 2008, International journal of oncology.

[147]  P. Calsou,et al.  Effect of double-strand break DNA sequence on the PARP-1 NHEJ pathway. , 2008, Biochemical and biophysical research communications.

[148]  Alan Ashworth,et al.  Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy , 2005, Nature.

[149]  R. Weissleder,et al.  In Vivo Imaging of β-Galactosidase Activity Using Far Red Fluorescent Switch , 2004, Cancer Research.

[150]  Jian Yu,et al.  BH3 mimetics to improve cancer therapy; mechanisms and examples. , 2007, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[151]  L. Karnitz,et al.  Pharmacological Abrogation of S-Phase Checkpoint Enhances the Anti-Tumor Activity of Gemcitabine In Vivo , 2007, Cell cycle.

[152]  J. Medema,et al.  Apoptosis and non-apoptotic deaths in cancer development and treatment response. , 2008, Cancer treatment reviews.

[153]  M. Rincón,et al.  Non-Classical P38 Map Kinase Functions: Cell Cycle Checkpoints and Survival , 2008, International journal of biological sciences.

[154]  Identification of a Highly Potent and Selective DNA-Dependent Protein Kinase (DNA-PK) Inhibitor (NU7441) by Screening of Chromenone Libraries. , 2005 .

[155]  M. Barbacid,et al.  Tumour biology: Senescence in premalignant tumours , 2005, Nature.

[156]  J. Schiro,et al.  DNA-dependent protein kinase inhibitors as drug candidates for the treatment of cancer. , 2003, Molecular cancer therapeutics.

[157]  S. Ashwell,et al.  DNA Damage Detection and Repair Pathways—Recent Advances with Inhibitors of Checkpoint Kinases in Cancer Therapy , 2008, Clinical Cancer Research.

[158]  A. Ashworth,et al.  Targeting the Double-Strand DNA Break Repair Pathway as a Therapeutic Strategy , 2006, Clinical Cancer Research.

[159]  J. Vialard,et al.  p53-Independent Regulation of p21Waf1/Cip1 Expression and Senescence by Chk2 , 2005, Molecular Cancer Research.

[160]  E. Broude Treatment-Induced Tumor Cell Senescence and Its Consequences , 2008 .

[161]  T. Lawrence,et al.  Role of checkpoint kinase 1 in preventing premature mitosis in response to gemcitabine. , 2005, Cancer research.

[162]  A. Carr,et al.  Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice , 2000, Current Biology.

[163]  C. Godon,et al.  Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis , 2006, Molecular Cancer Therapeutics.

[164]  E. Moler,et al.  CHIR-124, a Novel Potent Inhibitor of Chk1, Potentiates the Cytotoxicity of Topoisomerase I Poisons In vitro and In vivo , 2007, Clinical Cancer Research.

[165]  Jeremy M. Stark,et al.  53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks , 2010, Cell.

[166]  M. Yaffe,et al.  Kinases that control the cell cycle in response to DNA damage: Chk1, Chk2, and MK2. , 2009, Current opinion in cell biology.

[167]  C. Prives,et al.  p73 induction after DNA damage is regulated by checkpoint kinases Chk1 and Chk2. , 2004, Genes & development.

[168]  Bernd Giese,et al.  Targeting phosphoinositide 3-kinase: moving towards therapy. , 2008, Biochimica et biophysica acta.

[169]  N. Curtin,et al.  Effects of novel inhibitors of poly(ADP-ribose) polymerase-1 and the DNA-dependent protein kinase on enzyme activities and DNA repair , 2004, Oncogene.