Genotype-tailored ERK/MAPK pathway and HDAC inhibition rewires the apoptotic rheostat to trigger colorectal cancer cell death
- Author(s)
- Jenkins, LJ; Luk, IY; Fairlie, WD; Lee, EF; Palmieri, M; Schoffer, KL; Tan, T; Ng, I; Vukelic, N; Tran, S; Tse, JW; Nightingale, R; Alam, Z; Chionh, F; Iatropoulos, G; Ernst, M; Afshar-Sterle, S; Desai, J; Gibbs, P; Sieber, OM; Dhillon, AS; Tebbutt, NC; Mariadason, JM;
- Journal Title
- Molecular Cancer Therapeutics
- Publication Type
- epub ahead of print
- Abstract
- The EGFR/RAS/MEK/ERK signalling pathway (ERK/MAPK) is hyper-activated in most colorectal cancers (CRCs). A current limitation of inhibitors of this pathway is that they primarily induce cytostatic effects in CRC cells. Nevertheless, these drugs do induce expression of pro-apoptotic factors, suggesting they may prime CRC cells to undergo apoptosis. As histone deacetylase inhibitors (HDACi) induce expression of multiple pro-apoptotic proteins, we examined whether they could synergize with ERK/MAPK inhibitors to trigger CRC cell apoptosis. Combined MEK/ERK and HDAC inhibition synergistically induced apoptosis in CRC cell lines and patient-derived tumour organoids in vitro, and attenuated Apc-initiated adenoma formation in vivo. Mechanistically, combined MAPK/HDAC inhibition enhanced expression of the BH3-only pro-apoptotic 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 CRCs, by combining a HDAC inhibitor with either an EGFR, KRASG12C or BRAFV600 inhibitor in KRAS/BRAFWT; KRASG12C, BRAFV600E CRC 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. .
- Publisher
- AACR
- Research Division(s)
- Personalised Oncology
- PubMed ID
- 36343387
- Publisher's Version
- https://doi.org/10.1158/1535-7163.MCT-22-0101
- Open Access at Publisher's Site
https://doi.org/10.1158/1535-7163.MCT-22-0101- Terms of Use/Rights Notice
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Creation Date: 2022-12-13 03:12:47
Last Modified: 2022-12-13 03:30:21