Journal ArticleDOI
A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers
Bingnan Zhang,Kavya Ramkumar,R. Cardnell,C. Allison Stewart,Wei Lien Wang,Junya Fujimoto,Ignacio I. Wistuba,Lauren Averett Byers +7 more
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TLDR
Schlafen 11 (SLFN11) is a putative DNA/RNA helicase that induces irreversible replication block, which is emerging as an important regulator of cellular response to DNA damage as mentioned in this paper.Abstract:
DNA-damaging agents exploit increased genomic instability, a hallmark of cancer. Recently, inhibitors targeting the DNA damage response (DDR) pathways, such as PARP inhibitors, have also shown promising therapeutic potential. However, not all tumors respond well to these treatments, suggesting additional determinants of response are required. Schlafen 11 (SLFN11), a putative DNA/RNA helicase that induces irreversible replication block, is emerging as an important regulator of cellular response to DNA damage. Preclinical and emerging clinical trial data suggest that SLFN11 is a predictive biomarker of response to a wide range of therapeutics that cause DNA damage including platinum salts and topoisomerase I/II inhibitors, as well as PARP inhibitors, which has raised exciting possibilities for its clinical application. In this article, we review the function, prevalence, and clinical testing of SLFN11 in tumor biopsy samples and circulating tumor cells. We discuss mounting evidence of SLFN11 as a key predictive biomarker for a wide range of cancer therapeutics and as a prognostic marker across several cancer types. Furthermore, we discuss emerging areas of investigation such as epigenetic reactivation of SLFN11 and its role in activating immune response. We then provide perspectives on open questions and future directions in studying this important biomarker.read more
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Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11.
TL;DR: 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.
Journal ArticleDOI
Immunotherapy in Extensive-Stage Small Cell Lung Cancer.
Rola El Sayed,Normand Blais +1 more
TL;DR: In the first-line setting, immunotherapy has been a thriving concept that revolutionized treatment options in multiple malignancies, rendering previously untreatable diseases potentially curable as mentioned in this paper.
Journal ArticleDOI
Dynamic expression of Schlafen 11 (SLFN11) in circulating tumour cells as a liquid biomarker in small cell lung cancer
Bingnan Zhang,C. Allison Stewart,Qi Wang,Robert J. Cardnell,Pedro P. Rocha,Junya Fujimoto,Luisa M. Solis Soto,Runsheng Wang,V. Novegil,Peter Ansell,Lei He,Luisa Fernandez,Adam Jendrisak,Cole Gilbertson,Joseph D. Schonhoft,Jiyun Byun,Joshua Jones,J. Anderson,Ana Aparicio,Hai T. Tran,Marcelo V. Negrao,Jianjun Zhang,Wei-Lien Wang,Ignacio I. Wistuba,Jing Wang,Rick Wenstrup,Lauren Averett Byers,C. Gay +27 more
TL;DR: Schlafen 11 (SLFN11) was evaluated in tumour samples and characterised in circulating tumour cells (CTC) longitudinally to determine its potential role as a biomarker of response as discussed by the authors .
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.
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
How cells respond to interferons
TL;DR: The Janus kinases and signal transducers and activators of transcription, and many of the interferon-induced proteins, play important alternative roles in cells, raising interesting questions as to how the responses to the interFERons intersect with more general aspects of cellular physiology and how the specificity of cytokine responses is maintained.
Journal ArticleDOI
PARP inhibitors: Synthetic lethality in the clinic
TL;DR: Current knowledge of PARP inhibitors and potential ways to maximize their clinical effectiveness are discussed, and interesting lessons for the development of other therapies are provided.
Journal ArticleDOI
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.