Claudia Winkler1, Joshua Armenia2, Gemma N Jones3, Luis Tobalina2, Matthew J Sale4, Tudor Petreus5, Tarrion Baird3, Violeta Serra6, Anderson T Wang5, Alan Lau5, Mathew J Garnett7, Patricia Jaaks7, Elizabeth A Coker7, Andrew J Pierce3, Mark J O'Connor5, Elisabetta Leo8. 1. Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK. claudia.winkler@astrazeneca.com. 2. Bioinformatics and Data Science, Research and Early Development, Oncology R&D, AstraZeneca, Cambridge, UK. 3. Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK. 4. Signalling Programme, The Babraham Institute, Babraham Research Campus, Cambridge, CB22 3AT, Cambridge, UK. 5. Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK. 6. Experimental Therapeutics Group, Vall d' Hebron Institute of Oncology, Barcelona, Spain. 7. Wellcome Sanger Institute, Cambridge, UK. 8. Bioscience, Oncology R&D, AstraZeneca, Cambridge, UK. elisabetta.leo@astrazeneca.com.
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.
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.
Authors: Wanjuan Yang; Jorge Soares; Patricia Greninger; Elena J Edelman; Howard Lightfoot; Simon Forbes; Nidhi Bindal; Dave Beare; James A Smith; I Richard Thompson; Sridhar Ramaswamy; P Andrew Futreal; Daniel A Haber; Michael R Stratton; Cyril Benes; Ultan McDermott; Mathew J Garnett Journal: Nucleic Acids Res Date: 2012-11-23 Impact factor: 16.971
Authors: Alexandre André B A da Costa; Dipanjan Chowdhury; Geoffrey I Shapiro; Alan D D'Andrea; Panagiotis A Konstantinopoulos Journal: Nat Rev Drug Discov Date: 2022-10-06 Impact factor: 112.288
Authors: Bingnan Zhang; C Allison Stewart; Qi Wang; Robert J Cardnell; Pedro Rocha; Junya Fujimoto; Luisa M Solis Soto; Runsheng Wang; Veronica Novegil; Peter Ansell; Lei He; Luisa Fernandez; Adam Jendrisak; Cole Gilbertson; Joseph D Schonhoft; Jiyun Byun; Joshua Jones; Amanda K L Anderson; Ana Aparicio; Hai Tran; Marcelo V Negrao; Jianjun Zhang; Wei-Lien Wang; Ignacio I Wistuba; Jing Wang; Rick Wenstrup; Lauren A Byers; Carl M Gay Journal: Br J Cancer Date: 2022-04-19 Impact factor: 9.075
Authors: Yasuhisa Murai; Ukhyun Jo; Naoko Takebe; Yves Pommier; Junko Murai; Lisa M Jenkins; Shar-Yin N Huang; Sirisha Chakka; Lu Chen; Ken Cheng; Shinsaku Fukuda Journal: Cancer Res Date: 2021-04-16 Impact factor: 13.312
Authors: Marije E Weidema; Ingrid M E Desar; Melissa H S Hillebrandt-Roeffen; Anke E M van Erp; Mikio Masuzawa; Uta E Flucke; Winette T A van der Graaf; Yvonne M H Versleijen-Jonkers Journal: J Cancer Res Clin Oncol Date: 2021-06-03 Impact factor: 4.553
Authors: Bingnan Zhang; Kavya Ramkumar; Robert John Cardnell; Carl Michael Gay; C Allison Stewart; Wei-Lien Wang; Junya Fujimoto; Ignacio I Wistuba; Lauren Averett Byers Journal: Br J Cancer Date: 2021-07-22 Impact factor: 9.075
Authors: James M Cleary; Brian M Wolpin; Stephanie K Dougan; Srivatsan Raghavan; Harshabad Singh; Brandon Huffman; Nilay S Sethi; Jonathan A Nowak; Geoffrey I Shapiro; Andrew J Aguirre; Alan D D'Andrea Journal: Clin Cancer Res Date: 2021-07-20 Impact factor: 13.801
Authors: Ramazan Gundogdu; M Kadir Erdogan; Angeliki Ditsiou; Victoria Spanswick; Juan Jose Garcia-Gomez; John A Hartley; Fumiko Esashi; Alexander Hergovich; Valenti Gomez Journal: Cell Signal Date: 2021-08-05 Impact factor: 4.315