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  1. Evaluation Summary:

    This manuscript will be of interest to a broad audience of cancer biologists, especially those interested in esophageal cancer or treatment strategies involving ATR inhibition. It provides novel information about how FDA-approved antiretroviral compound Arbidol is a potential ATR inhibitor, which is of interest in the treatment of multiple tumor types. The key claims of the manuscript are supported by in silico, in vitro, and in vivo data.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The work by Yang, Ning et al. investigates the antitumor activity of FDA-approved broad-spectrum antiretroviral agent Arbidol using esophageal squamous cell carcinoma (ESCC) cell lines and suggests a novel role for Arbidol in the treatment of cancer, an application previously unexplored for this compound. The authors found that Arbidol inhibits the proliferation of ESCC cells in both in vitro and in vivo models. Mechanistically, they use phospho-proteomic data to show that this growth inhibition is resultant from modulation of the MCM-ATR axis. They next conducted a computational docking study and found that Arbidol binds ATR at ASN 2346 and ASN 2361, and upon mutating these residues in ATR, binding of Arbidol to ATR was less efficient. They also show that ATR is involved in MCM2 S108 phosphorylation and that Arbidol induces growth arrest at the G1 phase in a dose-dependent manner in ESCC cell lines. The authors show that knockdown of ATR leads to reduced ESCC cell growth, and they use TCGA to show that ATR is expressed at higher levels in esophageal carcinoma patients as compared to healthy controls. Importantly, Arbidol inhibited ESCC patient-derived xenograft tumor growth in a PDX mouse model. These data add important information about the potential ability of Arbidol to inhibit ATR which has implications for the treatment of esophageal cancer, and many other tumor types. Overall, the experiments conducted are logical and well-controlled, however some aspects of experimental design and statistical analysis need to be expanded upon.

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  3. Reviewer #2 (Public Review):

    This study by Yang et al described that a FDA-approved drug Arbidol targets ATR in an ATP competitive manner, which in turn impedes ESCC cells growth both in vitro and in vivo through affecting DNA replication pathway and arresting the cell cycle at G1 phase. Overall, the study is rationally-designed and the data are convincing. The experiments are well-controlled and their results are mostly clean and interesting.

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