Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11.
Reads0
Chats0
TLDR
In this article, the authors provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.Abstract:
Precision medicine aims to implement strategies based on the molecular features of tumors and optimized drug delivery to improve cancer diagnosis and treatment. DNA replication is a logical approach because it can be targeted by a broad range of anticancer drugs that are both clinically approved and in development. These drugs increase deleterious replication stress (RepStress); however, how to selectively target and identify the tumors with specific molecular characteristics are unmet clinical needs. Here, we provide background information on the molecular processes of DNA replication and its checkpoints, and discuss how to target replication, checkpoint, and repair pathways with ATR inhibitors and exploit Schlafen 11 (SLFN11) as a predictive biomarker.read more
Citations
More filters
Journal ArticleDOI
Discovery of small-molecule ATR inhibitors for potential cancer treatment: a patent review from 2014 to present
TL;DR: This article surveys the patents published since 2014 aiming to analyze the structural features of scaffolds and the patent space and discusses the recent clinical developments and provides perspectives on the challenges and the future directions.
Journal ArticleDOI
Reconsidering the mechanisms of action of PARP inhibitors based on clinical outcomes
Hiroshi Onji,Junko Murai +1 more
TL;DR: The reasons for variable indications of PARPis resulting from clinical outcomes are considered, the mechanisms of action for PARPIS as anticancer agents are reviewed and the importance of SLFN11 in PARPi sensitivity is shown.
Journal ArticleDOI
TOP1-DNA Trapping by Exatecan and Combination Therapy with ATR Inhibitor
Ukhyun Jo,Chen, Shih-Yu +1 more
TL;DR: In this paper , the molecular pharmacology of exatecan compared with the clinically approved topoisomerase I (TOP1) inhibitors and preclinical models for validating biomarkers and the combination of Exatecan with ataxia telangiectasia and Rad3-related kinase (ATR) inhibitors were reported.
Journal ArticleDOI
Integrative epigenomic analyses of small cell lung cancer cells demonstrates the clinical translational relevance of gene body methylation
Lőrinc S. Pongor,Camille Tlemsani,Fathi Elloumi,Yasuhiro Arakawa,Ukhyun Jo,Jacob M. Gross,Sara Mosavarpour,Sudhir Varma,Rahul K. Kollipara,Nitin Roper,Beverly A. Teicher,Mirit I. Aladjem,William C. Reinhold,Anish Thomas,John D. Minna,Jane E. Johnson,Yves Pommier +16 more
TL;DR: This paper examined global DNA methylation beyond the generally used promoter areas in human small cell lung cancer (SCLC) and find that gene body methylation is a robust positive predictor of gene expression.
Journal ArticleDOI
Structural, molecular, and functional insights into Schlafen proteins
Ukhyun Jo,Chen, Shih-Yu +1 more
TL;DR: Schlafen (SLFN) genes belong to a vertebrate gene family encoding proteins with high sequence homology and are involved in various cellular and tissue-specific processes, including DNA replication, proliferation, immune and interferon responses, viral infections, and sensitivity to DNA-targeted anticancer agents as mentioned in this paper .
References
More filters
Journal ArticleDOI
Hallmarks of cancer: the next generation.
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
Journal ArticleDOI
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity
Jordi Barretina,Giordano Caponigro,Nicolas Stransky,Kavitha Venkatesan,Adam A. Margolin,Adam A. Margolin,Sungjoon Kim,Christine D. Wilson,Joseph Lehar,Gregory V. Kryukov,Dmitriy Sonkin,Anupama Reddy,Manway Liu,Lauren Murray,Michael F. Berger,Michael F. Berger,John Monahan,Paula Morais,Jodi Meltzer,Adam Korejwa,Judit Jané-Valbuena,Judit Jané-Valbuena,Felipa A. Mapa,Joseph Thibault,Eva Bric-Furlong,Pichai Raman,Aaron Shipway,Ingo H. Engels,Jill Cheng,Guoying K. Yu,Jianjun Yu,Peter Aspesi,Melanie de Silva,Kalpana Jagtap,Michael D. Jones,Li Wang,Charlie Hatton,Emanuele Palescandolo,Supriya Gupta,Scott Mahan,Carrie Sougnez,Robert C. Onofrio,Ted Liefeld,Laura E. MacConaill,Wendy Winckler,Michael R. Reich,Nanxin Li,Jill P. Mesirov,Stacey Gabriel,Gad Getz,Kristin G. Ardlie,Vivien W. Chan,Vic E. Myer,Barbara L. Weber,Jeffrey A. Porter,Markus Warmuth,Peter Finan,Jennifer L. Harris,Matthew Meyerson,Matthew Meyerson,Todd R. Golub,Michael Morrissey,William R. Sellers,Robert Schlegel,Levi A. Garraway,Levi A. Garraway +65 more
TL;DR: The results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents and the generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of ‘personalized’ therapeutic regimens.
Journal ArticleDOI
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.
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.
Journal ArticleDOI
Systematic identification of genomic markers of drug sensitivity in cancer cells
Mathew J. Garnett,Elena J. Edelman,Sonja J. Heidorn,Christopher Greenman,Christopher Greenman,Anahita Dastur,King Wai Lau,Patricia Greninger,I. Richard Thompson,Xi Luo,Jorge Soares,Qingsong Liu,Francesco Iorio,Francesco Iorio,Didier Surdez,Li Chen,Randy J. Milano,Graham R. Bignell,Ah Ting Tam,Helen Davies,Jesse A. Stevenson,Syd Barthorpe,Stephen R. Lutz,Fiona Kogera,Karl P. Lawrence,Anne McLaren-Douglas,Xeni Mitropoulos,Tatiana Mironenko,Helen Thi,Laura Richardson,Wenjun Zhou,F Jewitt,Tinghu Zhang,Patrick O’Brien,Jessica L. Boisvert,Stacey Price,Wooyoung Hur,Wanjuan Yang,Xianming Deng,Adam Butler,Hwan Geun Choi,Jae Won Chang,José Baselga,Ivan Stamenkovic,Jeffrey A. Engelman,Sreenath V. Sharma,Sreenath V. Sharma,Olivier Delattre,Julio Saez-Rodriguez,Nathanael S. Gray,Jeffrey Settleman,P. Andrew Futreal,Daniel A. Haber,Daniel A. Haber,Michael R. Stratton,Sridhar Ramaswamy,Ultan McDermott,Cyril H. Benes +57 more
TL;DR: It was found that mutated cancer genes were associated with cellular response to most currently available cancer drugs, and systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.
Related Papers (5)
Clinical Candidates Targeting the ATR–CHK1–WEE1 Axis in Cancer
DNA damage response inhibitors: Mechanisms and potential applications in cancer therapy.
Laura Carrassa,Giovanna Damia +1 more