SLFN11 informs on standard of care and novel treatments in a wide range of cancer models.
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ICR Authors
Authors
Winkler, C
Armenia, J
Jones, GN
Tobalina, L
Sale, MJ
Petreus, T
Baird, T
Serra, V
Wang, AT
Lau, A
Garnett, MJ
Jaaks, P
Coker, EA
Pierce, AJ
O'Connor, MJ
Leo, E
Armenia, J
Jones, GN
Tobalina, L
Sale, MJ
Petreus, T
Baird, T
Serra, V
Wang, AT
Lau, A
Garnett, MJ
Jaaks, P
Coker, EA
Pierce, AJ
O'Connor, MJ
Leo, E
Document Type
Journal Article
Date
2021-03-02
Date Accepted
2020-11-11
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Citation
British journal of cancer, 2021, 124 (5), pp. 951 - 962
Source Title
Publisher
SPRINGERNATURE
ISSN
0007-0920
eISSN
1532-1827
Collections
Research Team
Target Biology and Genomic Instability
Target Biology and Genomic Instability
Target Biology and Genomic Instability