The underlying mechanism for the PARP and BRCA synthetic lethality: Clearing up the misunderstandings
TLDR
Alternative models that are not mutually exclusive are presented to explain the synthetic lethality between BRCA1/2 and PARP inhibitors and one such model proposes that PARP inhibition causes PARP‐1 to be trapped onto DNA repair intermediates, especially during base excision repair.About:
This article is published in Molecular Oncology.The article was published on 2011-08-01 and is currently open access. It has received 667 citations till now. The article focuses on the topics: Synthetic lethality & DNA repair.read more
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Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors
Junko Murai,Shar Yin N. Huang,Benu Brata Das,Amelie Renaud,Yiping Zhang,James H. Doroshow,Jiuping Ji,Shunichi Takeda,Yves Pommier +8 more
TL;DR: This study shows that PARP inhibitors trap the PARP1 and PARP2 enzymes at damaged DNA, providing a new mechanistic foundation for the rational application ofPARP inhibitors in cancer therapy.
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Playing the End Game: DNA Double-Strand Break Repair Pathway Choice
TL;DR: Recent insights are reviewed into the mechanisms that influence the choice between competing DSB repair pathways, how this is regulated during the cell cycle, and how imbalances in this equilibrium result in genome instability.
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Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation.
Jennifer K. Litton,Hope S. Rugo,Johannes Ettl,Sara A. Hurvitz,Anthony Gonçalves,Kyung Hun Lee,Louis Fehrenbacher,Rinat Yerushalmi,Lida A. Mina,Miguel Martin,Henri Roché,Young-Hyuck Im,Ruben G.W. Quek,Denka Markova,Iulia Cristina Tudor,Alison L. Hannah,Wolfgang Eiermann,Joanne L. Blum +17 more
TL;DR: Among patients with advanced breast cancer and a germline BRCA1/2 mutation, single‐agent talazoparib provided a significant benefit over standard chemotherapy with respect to progression‐free survival.
Journal ArticleDOI
Targeting the DNA Damage Response in Cancer
TL;DR: The recent approval of olaparib (Lynparza) represents the first medicine based on this principle, exploiting an underlying cause of tumor formation that also represents an Achilles' heel.
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DNA repair dysregulation from cancer driver to therapeutic target
TL;DR: First, to prevent or reverse therapy resistance; and second, using a synthetic lethal approach to specifically kill cancer cells that are dependent on a compensatory DNA repair pathway for survival in the context of cancer-associated oxidative and replicative stress are tested.
References
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A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1
Yoshio Miki,Jeff Swensen,Donna M Shattuck-Eidens,P. Andrew Futreal,Keith D Harshman,Sean V. Tavtigian,Qingyun Liu,Charles Cochran,L. Michelle Bennett,Wei Ding,Russell Bell,Judith Rosenthal,Charles E. Hussey,Thanh Tran,Melody McClure,Cheryl Frye,Tom Hattier,Robert Phelps,Astrid Haugen-Strano,Harold Katcher,Kazuko Yakumo,Zahra Gholami,Daniel Shaffer,Steven Stone,Steven Bayer,Christian Wray,Robert Bogden,Priya Dayananth,John R. Ward,Patricia N. Tonin,Steven A. Narod,Pam K. Bristow,Frank H. Norris,Leah M. Helvering,Paul Morrison,Paul Robert Rosteck,Mei Lai,J. Carl Barrett,Cathryn M. Lewis,Susan L. Neuhausen,Lisa A. Cannon-Albright,David E. Goldgar,Roger W. Wiseman,Alexander Kamb,Mark H. Skolnick +44 more
TL;DR: A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods.
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Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy
Hannah Farmer,Nuala McCabe,Christopher J. Lord,Andrew Tutt,Andrew Tutt,Damian A. Johnson,Tobias B. Richardson,Manuela Santarosa,Krystyna J. Dillon,Ian Hickson,Charlotte Knights,Niall M. B. Martin,Stephen P. Jackson,Graeme C. M. Smith,Alan Ashworth +14 more
TL;DR: BRCA1 or BRCA2 dysfunction unexpectedly and profoundly sensitizes cells to the inhibition of PARP enzymatic activity, resulting in chromosomal instability, cell cycle arrest and subsequent apoptosis, illustrating how different pathways cooperate to repair damage.
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Instability and decay of the primary structure of DNA
TL;DR: The spontaneous decay of DNA is likely to be a major factor in mutagenesis, carcinogenesis and ageing, and also sets limits for the recovery of DNA fragments from fossils.
Journal ArticleDOI
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Helen E. Bryant,Nilklas Schultz,Huw D. Thomas,Kayan M. Parker,Dan Flower,Elena Lopez,Suzanne Kyle,Mark Meuth,Nicola J. Curtin,Thomas Helleday,Thomas Helleday +10 more
TL;DR: It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone.
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Identification of the breast cancer susceptibility gene BRCA2
Richard Wooster,Graham R. Bignell,Johnathan M. Lancaster,Sally Swift,Sheila Seal,Jonathon Mangion,N. Collins,Simon G. Gregory,Curtis Gumbs,Gos Micklem +9 more
TL;DR: The identification of a gene in which six different germline mutations in breast cancer families that are likely to be due to BRCA2 are detected, and results indicate that this is the BRC a2 gene.