Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy

Pinki Chowdhury, Gregory E. Lin, Kang Liu, Yongcheng Song, Fang-Tsyr Lin and Weei-Chin Lin ()
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Pinki Chowdhury: Section of Hematology/Oncology, Baylor College of Medicine
Gregory E. Lin: Section of Hematology/Oncology, Baylor College of Medicine
Kang Liu: Section of Hematology/Oncology, Baylor College of Medicine
Yongcheng Song: Baylor College of Medicine
Fang-Tsyr Lin: Section of Hematology/Oncology, Baylor College of Medicine
Weei-Chin Lin: Section of Hematology/Oncology, Baylor College of Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract The progression of many solid tumours is driven by deregulation of multiple common pathways, particularly Rb, PI(3)K/Akt and p53. Prior studies identified TopBP1 as a key mediator for the oncogenic gain-of-function activities of mutant p53 (mutp53) in cancer. In Akt-hyperactive cancer, TopBP1 forms oligomers and represses E2F1-dependent apoptosis. Here we perform a molecular docking screening and identify a lead compound, calcein, capable of blocking TopBP1 oligomerization and p53 binding, resulting in re-activation of E2F1-dependent apoptosis and blockade of mutp53 gain-of-function. Calcein AM, the cell-permeable derivative of calcein, shows significant antitumour activity in a wide spectrum of cultured cancer cells harbouring high TopBP1 levels. These biochemical findings are recapitulated in breast cancer xenograft models. Thus, our study provides proof-of-concept evidence for targeting TopBP1, a convergent point of multiple pathways, as a cancer therapy.

Date: 2014
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DOI: 10.1038/ncomms6476

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