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Defining the susceptibility of colorectal cancers to BH3-mimetic compounds

Lookup NU author(s): Victoria Shuttleworth

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2020, Crown.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.

Publication metadata

Author(s): Luo M-J, Palmieri M, Riffkin CD, Sakthianandeswaren A, Djajawi TM, Hirokawa Y, Shuttleworth V, Segal DH, White CA, Nhu D, Lessene G, Lee M, Gibbs P, Huang DCS, Sieber OM, Gong J-N

Publication type: Article

Publication status: Published

Journal: Cell Death and Disease

Year: 2020

Volume: 11

Issue: 9

Print publication date: 01/09/2020

Online publication date: 10/09/2020

Acceptance date: 16/07/2020

Date deposited: 09/12/2020

ISSN (electronic): 2041-4889

Publisher: Springer Nature

URL: https://doi.org/10.1038/s41419-020-02815-0

DOI: 10.1038/s41419-020-02815-0

PubMed id: 32913182

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