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

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.

A Deep Learning Framework for Prediction of Clinical Drug Response of Cancer Patients and Identification of Drug Sensitivity Biomarkers using Preclinical Samples

“…This instability is one of the hallmarks of cancer and confers genetic diversity during tumorigenesis [24, 25]. Various studies have shown that the expression of this gene sensitizes cancer cells to many chemotherapeutic agents including cisplatin, oxaliplatin, irinotecan, gemcitabine, doxorubicin, and etoposide [26–30]. Epigenetically mediated suppression of SLFN11 via EZH2 contributes to acquired chemotherapy resistance, one that can be prevented and/or actively remodeled through targeting EZH2 [31].…”

“…The biomarkers identified by multiple drugs (Figure 4B) suggested important genes and signaling pathways that may play important roles in the mechanism of action of different drugs in cancer. Many genes identified during our study have been reported to have altered levels of expression in response to a given drug, especially SLFN11 for multiple chemotherapies [26–30], SALL4 for cisplatin [69], ABCB1 for taxane and doxorubicin [70, 71], PIGB for gemcitabine [72], and BAX to oxaliplatin [73]. These results suggest that our preclinical-to-clinical model could generate biologically relevant candidate genes and pathways for understanding mechanisms underlying drug resistance, and may offer additional combinational therapeutic strategies to overcome certain drug resistance.…”

PARP inhibition in UV-associated angiosarcoma preclinical models

“…Several preclinical studies provided evidence for the role of SLFN11 in cytotoxic effects of PARPi and chemotherapy in for instance Ewing sarcoma and lung cancer (Iwasaki et al 2019 ; Lok et al 2017 ; Tang et al 2015 ). However, a recent study showed no correlation between SLFN11 expression and olaparib activity in breast cancer cell lines and PDX models (Winkler et al 2021 ), stressing the need for cancer-specific experiments to examine SLFN11 as a biomarker. Thus far, the two reported clinical studies examining SLFN11 as a biomarker have not shown conclusive results.…”

The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response

“…1,2 Most recently, SLFN11 has also been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. [3][4][5][6][7] The study by Winkler and co-workers 8 in this issue of the British Journal of Cancer that accompanies this Editorial is both important and timely. Using an orthogonal multidisciplinary approach combining analyses of different cancer types using multiple models, combination strategies and mechanistic studies, it reinforces previously published work, while providing promising preclinical data supporting the use of SLFN11 as a predictive biomarker of DDA response (Fig.…”

“…Interestingly, two recent clinical trials reported that ATR or WEE1 inhibitor combinations with gemcitabine are potentially efficacious in ovarian and pancreatic cancer. 9,10 Winkler and co-authors 8 show in their preclinical models that these two tumour types present low or absent SLFN11 expression, highlighting the potential importance of SLFN11 in these cancer subtypes.…”