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|Ref Type||Journal Article|
|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.|
|Date||2014 Dec 01|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|