SLFN11 informs on standard of care and novel treatments in a wide range of cancer models

Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA an...

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Bibliographic Details
Published in:	British journal of cancer 2021-03, Vol.124 (5), p.951-962
Main Authors:	Winkler, Claudia, Armenia, Joshua, Jones, Gemma N, Tobalina, Luis, Sale, Matthew J, Petreus, Tudor, Baird, Tarrion, Serra, Violeta, Wang, Anderson T, Lau, Alan, Garnett, Mathew J, Jaaks, Patricia, Coker, Elizabeth A, Pierce, Andrew J, O'Connor, Mark J, Leo, Elisabetta
Format:	Article
Language:	eng
Subjects:	Animals Biomarkers Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - pathology Cancer therapies Chemotherapy CHK1 protein Deoxyribonucleic acid DNA DNA Damage Drug Resistance, Neoplasm Female Follow-Up Studies Humans Immunohistochemistry Mice Nuclear Proteins - genetics Nuclear Proteins - metabolism Patients Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology Protein Isoforms Protein Kinase Inhibitors - pharmacology Retrospective Studies Standard of Care Tissue Array Analysis Tumors Xenograft Model Antitumor Assays
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Summary:	Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors. An in-depth understanding of several aspects of its role as a biomarker in cancer is missing, as is a comprehensive analysis of the clinical significance of SLFN11 as a predictive biomarker to DDA and/or DNA damage-response inhibitor (DDRi) therapies. We used a multidisciplinary effort combining specific immunohistochemistry, pharmacology tests, anticancer combination therapies and mechanistic studies to assess SLFN11 as a potential biomarker for stratification of patients treated with several DDA and/or DDRi in the preclinical and clinical setting. SLFN11 protein associated with both preclinical and patient treatment response to DDA, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib in breast cancer. SLFN11-low/absent cancers were identified across different tumour types tested. Combinations of DDA with DDRi targeting the replication-stress response (ATR, CHK1 and WEE1) could re-sensitise SLFN11-absent/low cancer models to the DDA treatment and were effective in upper gastrointestinal and genitourinary malignancies. SLFN11 informs on the standard of care chemotherapy based on DDA and the effect of selected combinations with ATR, WEE1 or CHK1 inhibitor in a wide range of cancer types and models.
ISSN:	0007-0920 1532-1827