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- Title
SLFN11 informs on standard of care and novel treatments in a wide range of cancer models.
- 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
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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.<bold>Conclusion: </bold>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.
- Subjects
MEDICAL quality control; TISSUE arrays; PROTEINS; RESEARCH; DNA; NUCLEAR proteins; PROTEIN kinase inhibitors; ANIMAL experimentation; RESEARCH methodology; RETROSPECTIVE studies; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; RESEARCH funding; BREAST tumors; DRUG resistance in cancer cells; MICE; LONGITUDINAL method; PHARMACODYNAMICS
- Publication
British Journal of Cancer, 2021, Vol 124, Issue 5, p951
- ISSN
0007-0920
- Publication type
journal article
- DOI
10.1038/s41416-020-01199-4