SLFN11 informs on standard of care and novel treatments in a wide range of cancer models
Claudia Winkler,Joshua Armenia,Gemma N Jones,Luis Tobalina,Matthew J. Sale,Tudor Petreus,Tarrion Baird,Violeta Serra,Anderson T. Wang,Alan Lau,Mathew J. Garnett,Patricia Jaaks,Elizabeth A. Coker,Andrew J. Pierce,Mark J. O'Connor,Elisabetta Leo +15 more
TLDR
Schlafen 11 (SLFN11) has been linked with response to DNA-damaging agents (DDA) and PARP inhibitors as mentioned in this paper, but not to non-DDA or DDRi therapies, such as WEE1 inhibitor or olaparib.Abstract:
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.read more
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Adavosertib plus gemcitabine for platinum-resistant or platinum-refractory recurrent ovarian cancer: a double-blind, randomised, placebo-controlled, phase 2 trial.
Stephanie Lheureux,Mihaela C. Cristea,Jeff Bruce,Swati Garg,Michael Cabanero,Gina Mantia-Smaldone,Alexander B. Olawaiye,Susan Ellard,Johanne I Weberpals,Andrea E. Wahner Hendrickson,Gini F. Fleming,Stephen Welch,Neesha C. Dhani,Tracy Stockley,Prisni Rath,Katherine Karakasis,Gemma N Jones,Suzanne Jenkins,Jaime Rodriguez-Canales,Michael Tracy,Qian Tan,Valerie Bowering,Smitha Udagani,Lisa Wang,Charles A. Kunos,Eric Chen,Trevor J. Pugh,Amit M. Oza +27 more
TL;DR: In this paper, the Wee1 inhibitor combined with gemcitabine was evaluated in patients with high-grade serous ovarian cancer, a TP53-mutated tumour type with high replication stress.
Journal ArticleDOI
Ceralasertib (AZD6738), an Oral ATR Kinase Inhibitor, in Combination with Carboplatin in Patients with Advanced Solid Tumors: A Phase I Study.
Timothy A. Yap,Matthew G Krebs,Sophie Postel-Vinay,Anthony El-Khouiery,Jean-Charles Soria,Juanita Lopez,Alienor Berges,Sy Amy Cheung,Itziar Irurzun-Arana,Andrew Goldwin,Brunella Felicetti,Gemma N Jones,Alan Lau,Paul Frewer,Andrew J. Pierce,Glen Clack,Christine Stephens,Simon Smith,Emma Dean,Simon J. Hollingsworth +19 more
TL;DR: In this paper, the safety, tolerability, MTD, recommended phase II dose (RP2D), pharmacokinetic/pharmacodynamic profile, and preliminary antitumor activity of ceralasertib combined with carboplatin in patients with advanced solid tumors were reported.
Journal ArticleDOI
Targeting replication stress in cancer therapy
Alexandre André B A da Costa,Dipanjan Chowdhury,B. Shapiro,Alan D. D'Andrea,Panagiotis A. Konstantinopoulos +4 more
TL;DR: Current and emerging approaches for targeting replication stress in cancer, from preclinical and biomarker development to clinical trial evaluation are reviewed.
Journal ArticleDOI
The role of Schlafen 11 (SLFN11) as a predictive biomarker for targeting the DNA damage response.
TL;DR: SLFN11 has emerged as a promising predictor of sensitivity to DNA-damaging chemotherapies, and recently, been associated with sensitivity to PARP inhibition.
Journal ArticleDOI
SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243.
Yasuhisa Murai,Ukhyun Jo,Junko Murai,Lisa M. Miller Jenkins,Shar-yin N. Huang,Sirisha Chakka,Lu Chen,Ken Cheng,Shinsaku Fukuda,Naoko Takebe,Yves Pommier +10 more
TL;DR: In this article, the authors conducted a drug screen with the NCATS mechanistic drug library of 1,978 compounds in isogenic SLFN11-knockout (KO) and wild-type (WT) leukemia cell lines and found that TAK-243, a first-in-class ubiquitin activating enzyme UBA1 inhibitor in clinical development, causes preferential cytotoxicity in SLFN-11-KO cells; this effect is associated with claspin-mediated DNA replication inhibition by CHK1 independently of ATR.
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