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    Defining the susceptibility of colorectal cancers to BH3-mimetic compounds

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    Author
    Luo, M-J; Palmieri, M; Riffkin, CD; Sakthianandeswaren, A; Djajawi, TM; Hirokawa, Y; Shuttleworth, V; Segal, DH; White, CA; Nhu, D; ...
    Date
    2020-09-10
    Source Title
    Cell Death and Disease
    Publisher
    SPRINGERNATURE
    University of Melbourne Author/s
    Palmieri, Michelle; Sieber, Oliver; Lessene, Guillaume; Gibbs, Peter; Huang, David; White, Christine; Sakthianandeswaren, Anuratha; Segal, David; Luo, Mingjie; Riffkin, Chris; ...
    Affiliation
    Medical Biology (W.E.H.I.)
    Surgery (RMH)
    Metadata
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    Document Type
    Journal Article
    Citations
    Luo, M. -J., Palmieri, M., Riffkin, C. D., Sakthianandeswaren, A., Djajawi, T. M., Hirokawa, Y., Shuttleworth, V., Segal, D. H., White, C. A., Nhu, D., Lessene, G., Lee, M., Gibbs, P., Huang, D. C. S., Sieber, O. M. & Gong, J. -N. (2020). Defining the susceptibility of colorectal cancers to BH3-mimetic compounds. CELL DEATH & DISEASE, 11 (9), https://doi.org/10.1038/s41419-020-02815-0.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/251562
    DOI
    10.1038/s41419-020-02815-0
    Abstract
    Novel targets are required to improve the outcomes for patients with colorectal cancers. In this regard, the selective inhibitor of the pro-survival protein BCL2, venetoclax, has proven highly effective in several hematological malignancies. In addition to BCL2, potent and highly selective small molecule inhibitors of its relatives, BCLxL and MCL1, are now available, prompting us to investigate the susceptibility of colorectal cancers to the inhibition of one or more of these pro-survival proteins. While targeting BCLxL, but not BCL2 or MCL1, on its own had some impact, most (15/17) of the immortalized colorectal cancer cell lines studied were efficiently killed by the combined targeting of BCLxL and MCL1. Importantly, these in vitro findings were confirmed in a xenograft model and, interestingly, in all (5/5) patient derived tumor organoids evaluated. Our results lend strong support to the notion that BCLxL and MCL1 are highly promising targets for further evaluation in efforts to improve the treatment of colorectal cancers.

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