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Molecular Diagnostics

A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers

British Journal of Cancer volume 125, pages 1333–1340 (2021)Cite this article

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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.

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Fig. 1: During replication stress, SLFN11 binds to RPA and induces irreversible fork block which leads to cell death.
Fig. 2: SLFN11 expression in clinical tumor samples.
Fig. 3: Therapeutic vulnerabilities and regulation of SLFN11-mediated cell death.

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Acknowledgements

We would like to acknowledge Ms. Sunita Patterson for manuscript editing, and Lixia Diao, PhD for bioinformatics support.

Funding

This work was supported by: The NIH/NCI CCSG P30-CA016672 (Bioinformatics Shared Resource); NIH/NCI R01-CA207295; The Andrew Sabin Family Fellowship; and through generous philanthropic contributions to The University of Texas MD Anderson Lung Cancer Moon Shot Program.

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Authors and Affiliations

  1. Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bingnan Zhang

  2. Department of Thoracic-Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Kavya Ramkumar, Robert John Cardnell, Carl Michael Gay, C. Allison Stewart & Lauren Averett Byers

  3. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Wei-Lien Wang, Junya Fujimoto & Ignacio I. Wistuba

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BZ and LAB conceived the project. All authors contributed to the writing of the final manuscript.

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Dr. Byers serves on advisory committees for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol-Myers Squibb, Genentech, and Pfizer and has research support from AbbVie, AstraZeneca, GenMab, Sierra Oncology, Tolero Pharmaceuticals. Dr. Wistuba reports grants and personal fees from Genentech/Roche, grants and personal fees from Bayer, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from AstraZeneca/Medimmune, grants and personal fees from Pfizer, grants and personal fees from HTG Molecular, grants and personal fees from Merck, personal fees from GlaxoSmithKline, grants and personal fees from Guardant Health, personal fees from MSD, grants from Oncoplex, grants from DepArray, grants from Adaptive, grants from Adaptimmune, grants from EMD Serono, grants from Takeda, grants from Amgen, grants from Karus, grants from Johnson & Johnson, grants from Iovance, grants from 4D, grants from Novartis, grants from Oncocyte, grants from Akoya, personal fees from Flame, outside the submitted work.

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Zhang, B., Ramkumar, K., Cardnell, R.J. et al. A wake-up call for cancer DNA damage: the role of Schlafen 11 (SLFN11) across multiple cancers. Br J Cancer 125, 1333–1340 (2021). https://doi.org/10.1038/s41416-021-01476-w

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