Synthetic Lethal Interaction between Defective Homologous Recombination DNA Repair and PARP Inhibition

Öz

Human cells are equipped with a complex DNA damage response mechanism to deal with endogenously or exogenously induced genome damages. In the case of impaired DNA damage response functionality, cells start accumulating various DNA lesions which, if not repaired, threat genome stability. Although inefficient DNA damage response activity can promote neoplastic transformation, anti-cancer treatment resistance and serious side effects, any specific DDR dysfunctionality could serve as a biomarker to predict therapeutic response or a pharmacologic target to render cancer cells more vulnerable to chemotherapeutics. Poly (ADP-ribose) (PARP) enzymes participate in various cellular processes, including DNA single-strand break repair pathway. BRCA1/2 proteins play essential roles in homologous recombination DNA double-strand break repair pathway. Recent studies showed that cells with homologous recombination deficiency due to BRCA1/2 mutations become sensitive to PARP inhibitors. The successful clinical implementation of the synthetic lethal interaction between BRCA1/2 and PARP has motivated researchers to investigate other possible biomarkers to evaluate homologous recombination efficiency and untangle other potential synthetic lethal interactions to overcome PARP inhibitor resistance. In this review, we first summarize the current understanding of DNA damage response activated upon DNA double-strand break formation, then explain the synthetic lethality between homologous recombination-mediated repair and PARP inhibition.

Anahtar Kelimeler

• Personalised Cancer Treatment
• Homologues recombination
• PARP Inhibitors
• BRCA1/2
• DNA Damage Response (DDR) Mechanism
• DNA Hasar Yanıt (DDR) Mekanizması

Defektif Homolog Rekombinasyon DNA Tamiri ve PARP İnhibisyonu Arasındaki Sentetik Letal Etkileşim

Öz

İnsan hücreleri endojen ve eksojen nedenlerle oluşan genomik hasarlara karşı kompleks bir DNA hasar yanıt mekanizmasına sahiptir. Hücreler, DNA hasar yanıt işlevsizliği durumunda onarılmadıklarından genom stabilitesini tehdit eden çeşitli DNA lezyonlarını biriktirmeye başlar. Yetersiz DNA hasar yanıt aktivitesi; neoplastik transformasyona, antikanser ilaç direncine ve ilgili tedaviler neticesinde oluşan ciddi yan etkilere neden olmanın yanı sıra, tedavi yanıtının tahmininde kullanılabilir bir biyogösterge veya kanser hücrelerini mevcut tedavilere karşı daha duyarlı hale getirebilecek farmakolojik bir hedef olarak da kullanılabilmektedir. Poli (ADP-riboz) (PARP) enzimleri, DNA tek zincir kırıklarının onarılması dahil birçok hücresel mekanizmada rol oynamaktadır. BRCA1/2 proteinleri ise DNA çift zincir kırıklarının homolog rekombinasyon yolağıyla tamir edilmesinde görev almaktadır. Yapılan çalışmalar, BRCA1/2 mutasyonu neticesinde homolog rekombinasyon defektif hale gelen hücrelerin PARP inhibitörlerine karşı hassasiyet kazandığı göstermiştir. BRCA1/2 ve PARP arasında tanımlanan söz konusu sentetik letal etkileşimin başarılı klinik uygulaması, araştırmacıları homolog rekombinasyon durumunu bildirecek farklı biyogöstergeleri araştırmaya ve PARP inhibitör direncinin üstesinden gelmek için diğer potansiyel sentetik letal etkileşimleri ortaya çıkarmaya yönlendirmiştir. Bu derlemede öncelikle DNA hasar yanıt yolağının mevcut durumu özetlenmiş, sonrasında HR tamir sistemi ve PARP inhibisyonu arasındaki sentetik letalite anlatılmıştır.

Anahtar Kelimeler

• Kişiselleştirilmiş Kanser Tedavisi
• Homolog Rekombinasyon
• PARP İnhibitörleri
• BRCA1/2
• DNA Hasar Yanıt (DDR) Mekanizması

Kaynakça

1. Abbas, T., Keaton, M. A., Dutta, A. 2013. "Genomic instability in cancer.". Cold Spring Harbor perspectives in biology, 5(3), a012914.
2. Abida, W., Campbell, D., Patnaik, A., Sautois, B., Shapiro, J., Vogelzang, N. J., … Chowdhury, S. 2019. "Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): Updated analyses". Annals of Oncology.
3. Arena, S., Corti, G., Durinikova, E., Montone, M., Reilly, N. M., Russo, M., … Bardelli, A. 2020. "A subset of colorectal cancers with cross-sensitivity to olaparib and oxaliplatin". Clinical Cancer Research, 26(6), 1372–1384.
4. Ashworth, A., Lord, C. J. 2018. "Synthetic lethal therapies for cancer: what’s next after PARP inhibitors?". Nature Reviews Clinical Oncology, 15(9), 564–576.
5. Ashworth, A., Lord, C. J., Reis-Filho, J. S. 2011. "Genetic interactions in cancer progression and treatment.". Cell, 145(1), 30–38.
6. Bajrami, I., Frankum, J. R., Konde, A., Miller, R. E., Rehman, F. L., Brough, R., … Ashworth, A. 2014. "Genome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor Sensitivity". Cancer Research, 74(1), 287–297.
7. Bakkenist, C. J., Kastan, M. B. 2003. "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation". Nature, 421(6922), 499–506.
8. Barber, L. J., Sandhu, S., Chen, L., Campbell, J., Kozarewa, I., Fenwick, K., … Ashworth, A. 2013. "Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor". Journal of Pathology, 229(3), 422–429.

9. Bartek, J., Bartkova, J., Lukas, J. 2007. "DNA damage signalling guards against activated oncogenes and tumour progression". Oncogene, 26(56), 7773–7779.
10. Baxter, P. A., Su, J. M., Onar-Thomas, A., Billups, C. A., Li, X. N., Poussaint, T. Y., … Fouladi, M. 2020. "A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: A Pediatric Brain Tumor Consortium study". Neuro-Oncology.
11. Bhattacharjee, S., Nandi, S. 2017. "Synthetic lethality in DNA repair network: A novel avenue in targeted cancer therapy and combination therapeutics". IUBMB Life, 69(12), 929–937.
12. Bianconi, E., Piovesan, A., Facchin, F., Beraudi, A., Casadei, R., Frabetti, F., … Canaider, S. 2013. "An estimation of the number of cells in the human body". Annals of Human Biology.
13. Borchert, S., Wessolly, M., Schmeller, J., Mairinger, E., Kollmeier, J., Hager, T., … Mairinger, F. D. 2019. "Gene expression profiling of homologous recombination repair pathway indicates susceptibility for olaparib treatment in malignant pleural mesothelioma in vitro". BMC Cancer, 19(1), 1–12.
14. Bouwman, P., Aly, A., Escandell, J. M., Pieterse, M., Bartkova, J., van der Gulden, H., … Jonkers, J. 2010. "53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers". Nature Structural and Molecular Biology, 17(6), 688–695.
15. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., Jemal, A. 2018. "Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries". CA: A Cancer Journal for Clinicians, 68(6), 394–424.
16. Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., … Helleday, T. 2005. "Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase". Nature, 434(7035), 913–917.
17. Buisson, R., Dion-Côté, A.-M., Coulombe, Y., Launay, H., Cai, H., Stasiak, A. A. Z., … Masson, J.-Y. 2010. "Cooperation of breast cancer proteins PALB2 and piccolo BRCA2 in stimulating homologous recombination". Nature Structural & Molecular Biology, 17(10), 1247–1254.
18. Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., … Vogelstein, B. 1998. "Requirement for p53 and p21 to sustain G2 arrest after DNA damage.". Science (New York, N.Y.), 282(5393), 1497–1501.
19. Byrum, A. K., Vindigni, A., Mosammaparast, N. 2019. "Defining and Modulating ‘BRCAness’". Trends in Cell Biology, 29(9), 740–751.
20. Castroviejo‐Bermejo, M., Cruz, C., Llop‐Guevara, A., Gutiérrez‐Enríquez, S., Ducy, M., Ibrahim, Y. H., … Serra, V. 2018. " A RAD 51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation ". EMBO Molecular Medicine.
21. Chambliss, A. B., Chan, D. W. 2016. "Precision medicine: From pharmacogenomics to pharmacoproteomics". Clinical Proteomics.
22. Chapman, J. R., Taylor, M. R. G., Boulton, S. J. 2012. "Playing the End Game: DNA Double-Strand Break Repair Pathway Choice". Molecular Cell, 47(4), 497–510.
23. Ciardiello, F., Bang, Y.-J., Bendell, J., Cervantes, A., Brachmann, R., Zhang, K., … Shen, L. 2018. "A phase III, double-blind, randomized study of pamiparib versus placebo as maintenance therapy in patients with inoperable, locally advanced, or metastatic gastric cancer that responded to platinum-based first-line chemotherapy". Annals of Oncology.
24. Ciccia, A., Elledge, S. J. S. J., Adamo, A., Collis, S. J., Adelman, C. A., Silva, N., … Elledge, S. J. S. J. 2010. "The DNA Damage Response: Making It Safe to Play with Knives". Molecular Cell, 40(2), 179–204.
25. Cleary, J. M., Aguirre, A. J., Shapiro, G. I., D’Andrea, A. D. 2020. "Biomarker-Guided Development of DNA Repair Inhibitors". Molecular Cell, 18(78), 1070–1085.
26. Coleman, R. L., Fleming, G. F., Brady, M. F., Swisher, E. M., Steffensen, K. D., Friedlander, M., … Bookman, M. A. 2019. "Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer". New England Journal of Medicine.
27. Crabtree, J. S. 2019. "Pharmacogenomics". Içinde Clinical Precision Medicine: A Primer.
28. Curtin, N. J. 2013. "Inhibiting the DNA damage response as a therapeutic manoeuvre in cancer". British Journal of Pharmacology.
29. Curtin, Nicola J. 2012. "DNA repair dysregulation from cancer driver to therapeutic target". Nature Reviews Cancer, 12(12), 801–817.
30. D’Alessandro, A., Zolla, L. 2010. "Pharmacoproteomics: A chess game on a protein field". Drug Discovery Today.
31. Davies, H., Glodzik, D., Morganella, S., Yates, L. R., Staaf, J., Zou, X., … Nik-Zainal, S. 2017. "HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures". Nature Medicine.
32. de Bono, J., Mateo, J., Fizazi, K., Saad, F., Shore, N., Sandhu, S., … Hussain, M. 2020. "Olaparib for Metastatic Castration-Resistant Prostate Cancer". New England Journal of Medicine.
33. Deans, A. J., West, S. C. 2011. "DNA interstrand crosslink repair and cancer.". Nature reviews. Cancer, 11(7), 467–480.
34. Deckbar, D., Jeggo, P. A., Löbrich, M. 2011. "Understanding the limitations of radiation-induced cell cycle checkpoints". Critical Reviews in Biochemistry and Molecular Biology, 46(4), 271–283.
35. Densham, R. M., Garvin, A. J., Stone, H. R., Strachan, J., Baldock, R. A., Daza-Martin, M., … Morris, J. R. 2016. "Human BRCA1–BARD1 ubiquitin ligase activity counteracts chromatin barriers to DNA resection". Nature Structural & Molecular Biology, 23(7), 647–655.
36. Desai, A., Yan, Y., Gerson, S. L. 2018. "Advances in therapeutic targeting of the DNA damage response in cancer". DNA Repair.
37. Deshpande, R. A., Myler, L. R., Soniat, M. M., Makharashvili, N., Lee, L., Lees-Miller, S. P., … Paull, T. T. 2020. "DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP". Science Advances.
38. Dietlein, F., Thelen, L., Reinhardt, H. C. 2014. "Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches". Trends in Genetics, 30(8), 326–339.
39. Dréan, A., Lord, C. J., Ashworth, A. 2016. "PARP inhibitor combination therapy". Critical Reviews in Oncology/Hematology, 108, 73–85.
40. Ettl, J., Quek, R. G. W., Lee, K. H., Rugo, H. S., Hurvitz, S., Gonçalves, A., … Litton, J. K. 2018. "Quality of life with talazoparib versus physician’s choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: Patient-reported outcomes from the EMBRACA phase III trial". Annals of Oncology.
41. Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N. J., Johnson, D. A., Richardson, T. B., … Ashworth, A. 2005. "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy". Nature, 434(7035), 917–921.
42. Gogola, E., Duarte, A. A., de Ruiter, J. R., Wiegant, W. W., Schmid, J. A., de Bruijn, R., … Rottenberg, S. 2018. "Selective Loss of PARG Restores PARylation and Counteracts PARP Inhibitor-Mediated Synthetic Lethality". Cancer Cell, 33(6), 1078–1093.
43. Golan, T., Hammel, P., Reni, M., Van Cutsem, E., Macarulla, T., Hall, M. J., … Kindler, H. L. 2019. "Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer". New England Journal of Medicine.
44. Goldstein, M., Kastan, M. B. 2015. "The DNA Damage Response: Implications for Tumor Responses to Radiation and Chemotherapy". Annual Review of Medicine, 66(1), 129–143.
45. González-Martín, A., Pothuri, B., Vergote, I., DePont Christensen, R., Graybill, W., Mirza, M. R., … Monk, B. J. 2019. "Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer". New England Journal of Medicine.
46. Goodarzi, A. A., Jeggo, P. A. 2013. "The Repair and Signaling Responses to DNA Double-Strand Breaks". Içinde Advances in genetics (C. 82, ss. 1–45).
47. Haas, K. T., Lee, M. Y., Esposito, A., Venkitaraman, A. R. 2018. "Single-molecule localization microscopy reveals molecular transactions during RAD51 filament assembly at cellular DNA damage sites". Nucleic Acids Research.
48. Han, Y., Chen, M.-K., Wang, H.-L., Hsu, J. L., Li, C.-W., Chu, Y.-Y., … Hung, M.-C. 2019. "Synergism of PARP inhibitor fluzoparib (HS10160) and MET inhibitor HS10241 in breast and ovarian cancer cells.". American journal of cancer research.
49. Hanahan, D., Weinberg, R. A. 2000. "The Hallmarks of Cancer". Cell, 100(1), 57–70.
50. Hanahan, D., Weinberg, R. A. 2011. "Hallmarks of cancer: the next generation.". Cell, 144(5), 646–674.
51. Hanahan, D., Weinberg, R. A., Francisco, S. 2000. "The Hallmarks of Cancer Review University of California at San Francisco", 100, 57–70.
52. Harashima, H., Dissmeyer, N., Schnittger, A. 2013. "Cell cycle control across the eukaryotic kingdom". Trends in Cell Biology.
53. Helleday, T. 2011. "The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings". Molecular Oncology, 5(4), 387–393.
54. Helleday, T., Petermann, E., Lundin, C., Hodgson, B., Sharma, R. A. 2008. "DNA repair pathways as targets for cancer therapy". Nature Reviews Cancer, 8(3), 193–204.
55. Hess, S. 2013. "The emerging field of chemo- and pharmacoproteomics". Proteomics - Clinical Applications.
56. Hoeijmakers, J. H. J. 2009. "DNA Damage, Aging, and Cancer". New England Journal of Medicine, 361(15), 1475–1485.
57. Hoppe, M. M., Sundar, R., Tan, D. S. P., Jeyasekharan, A. D. 2018. "Biomarkers for Homologous Recombination Deficiency in Cancer". JNCI: Journal of the National Cancer Institute, 110(7), 704–713.
58. Hu, Y., Petit, S. A., Ficarro, S. B., Toomire, K. J., Xie, A., Lim, E., … Livingston, D. M. 2014. "PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination–mediated DNA repair". Cancer Discovery, 4(12), 1430–1447.
59. Huang, A., Garraway, L. A., Ashworth, A., Weber, B. 2020. "Synthetic lethality as an engine for cancer drug target discovery". Nature Reviews Drug Discovery, 19(1), 23–38.
60. Hühn, D., Bolck, H. A., Sartori, A. A. 2013. "Targeting DNA double-strand break signalling and repair: recent advances in cancer therapy.". Swiss medical weekly, 143(July), 1–14.
61. Jackson, S. P., Bartek, J. 2009. "The DNA-damage response in human biology and disease". Nature, 461(7267), 1071–1078.
62. Jackson, S. P., Helleday, T. 2016. "Drugging DNA repair". Science, 352(6290), 1178–1179.
63. Jamal-Hanjani, M., Quezada, S. A., Larkin, J., Swanton, C. 2015. "Translational implications of tumor heterogeneity". Clinical Cancer Research.
64. Jasin, M., Rothstein, R. 2013. "Repair of Strand Breaks by Homologous Recombination". Cold Spring Harbor Perspectives in Biology, 5(11), a012740–a012740.
65. Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C. M., Lukas, J., Jackson, S. P. 2006. "ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks". Nature Cell Biology, 8(1), 37–45.
66. Jelinic, P., Levine, D. A. 2014. "New insights into PARP inhibitors’ effect on cell cycle and homology-directed DNA damage repair". Molecular Cancer Therapeutics, 13(6), 1645–1654.
67. Jensen, R. B., Carreira, A., Kowalczykowski, S. C. 2010. "Purified human BRCA2 stimulates RAD51-mediated recombination". Nature.
68. Kastan, M. B., Bartek, J. 2004. "Cell-cycle checkpoints and cancer". Nature, 432(7015), 316–323.
69. Kaufman, B., Shapira-Frommer, R., Schmutzler, R. K., Audeh, M. W., Friedlander, M., Balmaña, J., … Domchek, S. M. 2015. "Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation". Journal of Clinical Oncology.
70. Khanna, K. K., Jackson, S. P. 2001. "DNA double-strand breaks: signaling, repair and the cancer connection". Nature Genetics, 27(3), 247–254.
71. Kobayashi, J., Tauchi, H., Sakamoto, S., Nakamura, A., Morishima, K., Matsuura, S., … Komatsu, K. 2002. "NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT domain", 12(21).
72. Konstantinopoulos, P. A., Ceccaldi, R., Shapiro, G. I., D’Andrea, A. D. 2015. "Homologous recombination deficiency: Exploiting the fundamental vulnerability of ovarian cancer". Cancer Discovery, 5(11), 1137–1154.
73. Krejci, L., Altmannova, V., Spirek, M., Zhao, X. 2012. "Homologous recombination and its regulation.". Nucleic acids research, 40(13), 5795–5818.
74. Krishnakumar, R., Kraus, W. L. 2010. "The PARP Side of the Nucleus: Molecular Actions, Physiological Outcomes, and Clinical Targets". Molecular Cell, 39(1), 8–24.
75. Kulaberoglu, Y., Gundogdu, R. and Hergovich, A. 2016. "The Role of p53/p21/p16 in DNA-Damage Signaling and DNA Repair". Içinde Genome Stability (ss. 243–253).
76. Lee, J.-H., Paull, T. T. 2004. "Direct Activation of the ATM Protein Kinase by the Mre11/Rad50/Nbs1 Complex". Science, 304(5667), 93–96.
77. Lee, J. H., Paull, T. T. 2005. "ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex". Science, 308(5721), 551–554.
78. Li, S., Topatana, W., Juengpanich, S., Cao, J., Hu, J., Zhang, B., … Chen, M. 2020. "Development of synthetic lethality in cancer: molecular and cellular classification". Signal Transduction and Targeted Therapy, 5(1).
79. Lindahl, T, Barnes, D. E. 2000. "Repair of endogenous DNA damage.". Cold Spring Harbor symposia on quantitative biology, 65, 127–133.
80. Lindahl, Tomas, Nyberg, B. 1972. "Rate of depurination of native deoxyribonucleic acid". Biochemistry, 11(19), 3610–3618.
81. Loeb, L. A., Harris, C. C. 2008. "Advances in chemical carcinogenesis: A historical review and prospective". Cancer Research, 68(17), 6863–6872.
82. Lord, C. J., Ashworth, A. 2013. "Mechanisms of resistance to therapies targeting BRCA-mutant cancers". Nature Medicine, 19(11), 1381–1388.
83. Lord, C. J., Ashworth, A. 2016. "BRCAness revisited". Nature Reviews Cancer, 16(2), 110–120.
84. Lord, C. J., Ashworth, A. 2017. "PARP inhibitors: Synthetic lethality in the clinic". Science, 355(6330), 1152–1158.
85. Lord, C. J., Tutt, A. N. J., Ashworth, A. 2015. "Synthetic Lethality and Cancer Therapy: Lessons Learned from the Development of PARP Inhibitors". Annual Review of Medicine, 66(1), 455–470.
86. Luo, J., Solimini, N. L., Elledge, S. J. 2009. "Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction". Cell, 136(5), 823–837.
87. Ma, M., Rodriguez, A., Sugimoto, K. 2020. "Activation of ATR-related protein kinase upon DNA damage recognition". Current Genetics.
88. Maréchal, A., Zou, L. 2015. "RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response". Cell Research.
89. Mateo, J., Lord, C. J., Serra, V., Tutt, A., Balmaña, J., Castroviejo-Bermejo, M., … De Bono, J. S. 2019. "A decade of clinical development of PARP inhibitors in perspective". Annals of Oncology, 30(9), 1437–1447.
90. Matsuoka, S., Ballif, B. A., Smogorzewska, A., McDonald, E. R., Hurov, K. E., Luo, J., … Elledge, S. J. 2007. "ATM and ATR Substrate Analysis Reveals Extensive Protein Networks Responsive to DNA Damage". Science, 316(5828), 1160–1166.
91. Menendez, D., Inga, A., Resnick, M. A. 2009. "The expanding universe of p53 targets". Nature Reviews Cancer, 9(10), 724–737.
92. Mirza, M. R., Monk, B. J., Herrstedt, J., Oza, A. M., Mahner, S., Redondo, A., … Matulonis, U. A. 2016. "Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer". New England Journal of Medicine.
93. Moore, K., Colombo, N., Scambia, G., Kim, B.-G., Oaknin, A., Friedlander, M., … DiSilvestro, P. 2018. "Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer". New England Journal of Medicine.
94. Moore, K. N., Secord, A. A., Geller, M. A., Miller, D. S., Cloven, N., Fleming, G. F., … Monk, B. J. 2019. "Niraparib monotherapy for late-line treatment of ovarian cancer (QUADRA): a multicentre, open-label, single-arm, phase 2 trial". The Lancet Oncology.
95. Morales, J. C., Li, L., Fattah, F. J., Dong, Y., Bey, E. A., Patel, M., … Boothman, D. A. 2014. "Review of poly (ADP-ribose) polymerase (PARP) mechanisms of action and rationale for targeting in cancer and other diseases". Critical Reviews in Eukaryotic Gene Expression, 24(1), 15–28.
96. Murai, J., Huang, S. -y. N., Das, B. B., Renaud, A., Zhang, Y., Doroshow, J. H., … Pommier, Y. 2012. "Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors". Cancer Research, 72(21), 5588–5599.
97. Nandal, S., Burt, T. 2017. "Integrating pharmacoproteomics into early-phase clinical development: State-of-the-art, challenges, and recommendations". International Journal of Molecular Sciences.
98. Negrini, S., Gorgoulis, V. G., Halazonetis, T. D. 2010. "Genomic instability — an evolving hallmark of cancer". Nature Reviews Molecular Cell Biology, 11(3), 220–228.
99. Nickoloff, J. A., Jones, D., Lee, S. H., Williamson, E. A., Hromas, R. 2017. "Drugging the Cancers Addicted to DNA Repair". Journal of the National Cancer Institute, 109(11).
100. Noordermeer, S. M., van Attikum, H. 2019. "PARP Inhibitor Resistance: A Tug-of-War in BRCA-Mutated Cells". Trends in Cell Biology, 29(10), 820–834.
101. Norquist, B., Wurz, K. A., Pennil, C. C., Garcia, R., Gross, J., Sakai, W., … Swisher, E. M. 2011. "Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas". Journal of Clinical Oncology, 29(22), 3008–3015.
102. O’Connor, M. J. 2015. "Targeting the DNA Damage Response in Cancer". Molecular Cell, 60(4), 547–560.
103. Oza, A. M., Tinker, A. V., Oaknin, A., Shapira-Frommer, R., McNeish, I. A., Swisher, E. M., … Kristeleit, R. S. 2017. "Antitumor activity and safety of the PARP inhibitor rucaparib in patients with high-grade ovarian carcinoma and a germline or somatic BRCA1 or BRCA2 mutation: Integrated analysis of data from Study 10 and ARIEL2". Gynecologic Oncology.
104. Pagliarini, R., Shao, W., Sellers, W. R. 2015. "Oncogene addiction: pathways of therapeutic response, resistance, and road maps toward a cure". EMBO reports, 16(3), 280–296.
105. Panier, S., Durocher, D. 2013. "Push back to respond better: regulatory inhibition of the DNA double-strand break response". Nature Reviews Molecular Cell Biology, 14(10), 661–672.
106. Paull, T. T. 2015. "Mechanisms of ATM activation". Annual Review of Biochemistry, 84, 711–738.
107. Pettitt, S. J., Krastev, D. B., Brandsma, I., Dréan, A., Song, F., Aleksandrov, R., … Lord, C. J. 2018. "Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance". Nature Communications, 9(1), 1849.
108. Pilié, P. G., Gay, C. M., Byers, L. A., O’Connor, M. J., Yap, T. A. 2019. "PARP inhibitors: Extending benefit beyond BRCA-mutant cancers". Clinical Cancer Research, 25(13), 3759–3771.
109. Pilié, P. G., Tang, C., Mills, G. B., Yap, T. A. 2019. "State-of-the-art strategies for targeting the DNA damage response in cancer". Nature Reviews Clinical Oncology.
110. Pines, A., Vrouwe, M. G., Marteijn, J. A., Typas, D., Luijsterburg, M. S., Cansoy, M., … Mullenders, L. 2012. "PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1". Journal of Cell Biology, 199(2), 235–249.
111. Relling, M. V., Evans, W. E. 2015. "Pharmacogenomics in the clinic". Nature.
112. Robson, M. E., Tung, N., Conte, P., Im, S. A., Senkus, E., Xu, B., … Domchek, S. M. 2019. "OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician’s choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer". Annals of Oncology.
113. Roden, D. M., McLeod, H. L., Relling, M. V., Williams, M. S., Mensah, G. A., Peterson, J. F., Van Driest, S. L. 2019. "Pharmacogenomics". The Lancet.
114. Rose, M., Burgess, J. T., O’Byrne, K., Richard, D. J., Bolderson, E. 2020. "PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance". Frontiers in Cell and Developmental Biology, 8(September), 1–22.
115. Settleman, J. 2012. "Oncogene addiction". Current Biology, 22(2), 43–44.
116. Sharma, S. V., Settleman, J. 2007. "Oncogene addiction: Setting the stage for molecularly targeted cancer therapy". Genes and Development, 21(24), 3214–3231.
117. Simhadri, S., Vincelli, G., Huo, Y., Misenko, S., Foo, T. K., Ahlskog, J., … Xia, B. 2019. "PALB2 connects BRCA1 and BRCA2 in the G2/M checkpoint response". Oncogene, 38(10), 1585–1595.
118. Somlo, G., Frankel, P. H., Luu, T. H., Ma, C., Arun, B., Garcia, A., … Weitzel, J. N. 2013. "Efficacy of the combination of ABT-888 (veliparib) and carboplatin in patients with BRCA-associated breast cancer.". Journal of Clinical Oncology.
119. Speidel, D. 2015. "The role of DNA damage responses in p53 biology". Archives of Toxicology, 89(4), 501–517.
120. Stover, E. H., Konstantinopoulos, P. A., Matulonis, U. A., Swisher, E. M. 2016. "Biomarkers of response and resistance to DNA repair targeted therapies". Clinical Cancer Research, 22(23), 5651–5660.
121. Sy, S. M. H., Huen, M. S. Y., Chen, J. 2009. "PALB2 is an integral component of the BRCA complex required for homologous recombination repair". Proceedings of the National Academy of Sciences of the United States of America, 28(106), 7155–7160.
122. Syed, A., Tainer, J. A. 2018. "The MRE11-RAD50-NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair". Annual Review of Biochemistry, 87, 263–294.
123. Tisi, R., Vertemara, J., Zampella, G., Longhese, M. P. 2020. "Functional and structural insights into the MRX/MRN complex, a key player in recognition and repair of DNA double-strand breaks". Computational and Structural Biotechnology Journal.
124. Topatana, W., Juengpanich, S., Li, S., Cao, J., Hu, J., Lee, J., … Cai, X. 2020. "Advances in synthetic lethality for cancer therapy: Cellular mechanism and clinical translation". Journal of Hematology and Oncology, 13(1), 1–22.
125. Trenner, A., Sartori, A. A. 2019. "Harnessing DNA Double-Strand Break Repair for Cancer Treatment". Frontiers in Oncology, 9(1388), 1–10.
126. Turner, N. C., Lord, C. J., Iorns, E., Brough, R., Swift, S., Elliott, R., … Ashworth, A. 2008. "A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor". EMBO Journal.
127. Turner, N., Tutt, A., Ashworth, A. 2004. "Hallmarks of “BRCAness” in sporadic cancers". Nature Reviews Cancer.
128. Vilenchik, M. M., Knudson, A. G. 2003. "Endogenous DNA double-strand breaks: Production, fidelity of repair, and induction of cancer". Proceedings of the National Academy of Sciences, 100(22), 12871–12876.
129. Wahl, G. M., Linke, S. P., Paulson, T. G., Huang, L. C. 1997. "Maintaining genetic stability through TP53 mediated checkpoint control.". Cancer surveys, 29, 183–219.
130. Weinstein, I. B., Joe, A., Felsher, D. 2008. "Oncogene Addiction". Cancer Research, 68(9), 3077–3080.
131. Weinstein, I. Bernard, Joe, A. K. 2006. "Mechanisms of Disease: Oncogene addiction - A rationale for molecular targeting in cancer therapy". Nature Clinical Practice Oncology, 3(8), 448–457.
132. Wheeler, H. E., Maitland, M. L., Dolan, M. E., Cox, N. J., Ratain, M. J. 2013. "Cancer pharmacogenomics: Strategies and challenges". Nature Reviews Genetics.
133. Whirl-Carrillo, M., McDonagh, E. M., Hebert, J. M., Gong, L., Sangkuhl, K., Thorn, C. F., … Klein, T. E. 2012. "Pharmacogenomics knowledge for personalized medicine". Clinical Pharmacology and Therapeutics.
134. Yao, Y., Dai, W. 2014. "Genomic Instability and Cancer.". Journal of carcinogenesis & mutagenesis, 5.
135. Yata, K., Lloyd, J., Maslen, S., Bleuyard, J. Y., Skehel, M., Smerdon, S. J., Esashi, F. 2012. "Plk1 and CK2 Act in Concert to Regulate Rad51 during DNA Double Strand Break Repair". Molecular Cell, 45(3), 371–383.
136. Zhao, Q., Lan, T., Su, S., Rao, Y. 2019. "Induction of apoptosis in MDA-MB-231 breast cancer cells by a PARP1-targeting PROTAC small molecule". Chemical Communications, 55(3), 369–372.
137. Zhao, W., Hu, H., Mo, Q., Guan, Y., Li, Y., Du, Y., Li, L. 2019. "Function and mechanism of combined PARP-1 and BRCA genes in regulating the radiosensitivity of breast cancer cells.". International journal of clinical and experimental pathology.
138. Zugazagoitia, J., Guedes, C., Ponce, S., Ferrer, I., Molina-Pinelo, S., Paz-Ares, L. 2016. "Current Challenges in Cancer Treatment". Clinical Therapeutics.