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Ref Type Journal Article
PMID (25269479)
Authors Jossé R, Martin SE, Guha R, Ormanoglu P, Pfister TD, Reaper PM, Barnes CS, Jones J, Charlton P, Pollard JR, Morris J, Doroshow JH, Pommier Y
Title ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses.
Journal Cancer research
Vol 74
Issue 23
Date 2014 Dec 01
URL
Abstract Text Camptothecin and its derivatives, topotecan and irinotecan, are specific topoisomerase I (Top1) inhibitors and potent anticancer drugs killing cancer cells by producing replication-associated DNA double-strand breaks, and the indenoisoquinoline LMP-400 (indotecan) is a novel Top1 inhibitor in clinical trial. To develop novel drug combinations, we conducted a synthetic lethal siRNA screen using a library that targets nearly 7,000 human genes. Depletion of ATR, the main transducer of replication stress, came as a top candidate gene for camptothecin synthetic lethality. Validation studies using ATR siRNA and the ATR inhibitor VE-821 confirmed marked antiproliferative synergy with camptothecin and even greater synergy with LMP-400. Single-cell analyses and DNA fiber combing assays showed that VE-821 abrogates the S-phase replication elongation checkpoint and the replication origin-firing checkpoint induced by camptothecin and LMP-400. As expected, the combination of Top1 inhibitors with VE-821 inhibited the phosphorylation of ATR and Chk1; however, it strongly induced γH2AX. In cells treated with the combination, the γH2AX pattern changed over time from the well-defined Top1-induced damage foci to an intense peripheral and diffuse nuclear staining, which could be used as response biomarker. Finally, the clinical derivative of VE-821, VX-970, enhanced the in vivo tumor response to irinotecan without additional toxicity. A key implication of our work is the mechanistic rationale and proof of principle it provides to evaluate the combination of Top1 inhibitors with ATR inhibitors in clinical trials.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Berzosertib Berzosertib 6 6
Drug Name Trade Name Synonyms Drug Classes Drug Description
Berzosertib VX-970|VE-822|M6620 ATR Inhibitor 10 Berzosertib (VX-970) is a small molecule inhibitor of ATR, which may enhance the sensitivity of chemotherapeutic agents resulting in antitumor activity (PMID: 25269479, PMID: 32109490).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown colorectal adenocarcinoma not applicable Berzosertib + Irinotecan Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of VX-970 and Camptosar (irinotecan) synergized to inhibit proliferation of a colorectal adenocarcinoma cell line in culture and to inhibit tumor growth in a human colorectal adenocarcinoma cell line xenograft model (PMID: 25269479). 25269479