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Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death

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journal contribution
posted on 2023-05-12, 02:26 authored by Laura JenkinsLaura Jenkins, Ian LukIan Luk, Walter FairlieWalter Fairlie, Erinna LeeErinna Lee, M Palmieri, Kael Schoffer, T Tan, Irvin Ng, Natalia VukelicNatalia Vukelic, Sharon TranSharon Tran, Janson Tse, Rebecca NightingaleRebecca Nightingale, Zakia AlamZakia Alam, Fiona ChionhFiona Chionh, Georgios IatropoulosGeorgios Iatropoulos, Matthias ErnstMatthias Ernst, S Afshar-Sterle, J Desai, P Gibbs, OM Sieber, Amardeep Dhillon, Niall TebbuttNiall Tebbutt, John MariadasonJohn Mariadason
The EGFR/RAS/MEK/ERK signaling pathway (ERK/MAPK) is hyperactivated in most colorectal cancers. A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in colorectal cancer cells. Nevertheless, these drugs do induce expression of proapoptotic factors, suggesting they may prime colorectal cancer cells to undergo apoptosis. As histone deacetylase inhibitors (HDACis) induce expression of multiple proapoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger colorectal cancer cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in colorectal cancer cell lines and patient-derived tumor organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only proapoptotic proteins BIM and BMF, and their knockdown significantly attenuated MAPK/HDAC inhibitor-induced apoptosis. Importantly, we demonstrate that the paradigm of combined MAPK/HDAC inhibitor treatment to induce apoptosis can be tailored to specific MAPK genotypes in colorectal cancers, by combining an HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT; KRASG12C, BRAFV600E colorectal cancer cell lines, respectively. These findings identify a series of ERK/MAPK genotype-tailored treatment strategies that can readily undergo clinical testing for the treatment of colorectal cancer.

Funding

This project was supported by the Tour de Cure Senior Research grant (17-ONJC-RS-05) and the Operational Infrastructure Support Program, Victorian Government, Australia. L.J. Jenkins was supported by La Trobe University Australian Postgraduate Awards. G. Iatropoulos, I. Ng, and Z. Alam were supported by La Trove University Postgraduate Research Scholarship. The patient-derived tumor organoid study was supported by the Stafford Fox Medical Research Foundation. J.M. Mariadason (1046092) and O.M. Sieber (1136119) were supported by National Health and Medical Research Council (NHMRC) Senior Research Fellowships.

History

Publication Date

2023-01-03

Journal

Molecular Cancer Therapeutics

Volume

22

Issue

1

Pagination

11p. (p. 52-62)

Publisher

American Association for Cancer Research

ISSN

1535-7163

Rights Statement

This open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. © 2022 The Authors.