Targeting the DNA Damage Response in Cancer
TLDR
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.About:
This article is published in Molecular Cell.The article was published on 2015-11-19 and is currently open access. It has received 964 citations till now. The article focuses on the topics: Olaparib & Targeted therapy.read more
Citations
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Journal ArticleDOI
Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer
Kathleen N. Moore,Nicoletta Colombo,Giovanni Scambia,Byoung Gie Kim,Ana Oaknin,Michael Friedlander,Alla Lisyanskaya,Anne Floquet,Alexandra Leary,Gabe S. Sonke,Charlie Gourley,Susana Banerjee,Amit M. Oza,Antonio González-Martín,Carol Aghajanian,William H. Bradley,Cara Mathews,Joyce F. Liu,Elizabeth S. Lowe,Ralph Bloomfield,Paul DiSilvestro +20 more
TL;DR: The use of maintenance therapy with olaparib provided a substantial benefit with regard to progression‐free survival among women with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation, with a 70% lower risk of disease progression or death with olAParib than with placebo.
Journal ArticleDOI
Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer
Talia Golan,Pascal Hammel,Michele Reni,Eric Van Cutsem,Teresa Macarulla,Michael J. Hall,Joon Oh Park,Daniel Hochhauser,Dirk Arnold,Do Youn Oh,Anke Reinacher-Schick,Giampaolo Tortora,Giampaolo Tortora,Hana Algül,Eileen M. O'Reilly,David McGuinness,Karen Y. Cui,Katia Schlienger,Gershon Y. Locker,Hedy L. Kindler +19 more
TL;DR: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo, and there was no significant between-group difference in health-related quality of life.
Journal ArticleDOI
ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response.
TL;DR: A historical perspective of their discovery is provided and their established functions in sensing and responding to genotoxic stress are discussed, as well as emerging non-canonical roles and how knowledge of ATM, ATR, and DNA-PK is being translated to benefit human health.
Journal ArticleDOI
Olaparib for metastatic castration-resistant prostate cancer
Johann S. de Bono,Joaquin Mateo,Karim Fizazi,Fred Saad,Neal D. Shore,Shahneen Sandhu,Kim N. Chi,Oliver Sartor,Neeraj Agarwal,David Olmos,Antoine Thiery-Vuillemin,Przemyslaw Twardowski,Niven Mehra,C. Goessl,Jinyu Kang,J. Burgents,W. Wu,Alexander Kohlmann,Carrie A. Adelman,Maha Hussain +19 more
TL;DR: In men with metastatic castration-resistant prostate cancer who had disease progression while receiving enzalutamide or abiraterone and who had alterations in genes with a role in homologous recombination repair, olaparib was associated with longer progression-free survival and better measures of response and patient-reported end points than either enzalUTamide or monotherapy.
Journal ArticleDOI
State-of-the-art strategies for targeting the DNA damage response in cancer
TL;DR: The authors review the progress made to date with PARP inhibitors, describe the expanding landscape of novel anticancer therapies targeting the DNA damage response and potential predictive biomarkers, mechanisms of resistance and combinatorial strategies are discussed.
References
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PD-1 Blockade in Tumors with Mismatch-Repair Deficiency
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TL;DR: This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab, and high somatic mutation loads were associated with prolonged progression-free survival.
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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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The DNA-damage response in human biology and disease
Stephen P. Jackson,Jiri Bartek +1 more
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
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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.