Reference Detail

Ref Type

Journal Article

PMID

(36343387)

Authors

Jenkins LJ, Luk IY, Fairlie WD, Lee EF, Palmieri M, Schoffer KL, Tan T, Ng I, Vukelic N, Tran S, Tse JWT, 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

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	22	1	2023 Jan 03	52-62	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	sensitive	Mocetinostat + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Mocetinostat (MGCD0103) resulted in greater apoptotic activity compared to either agent alone in a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 36343387).	36343387
BRAF V600E	colorectal cancer	sensitive	Trametinib + Vorinostat	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Zolinza (vorinostat) resulted in greater apoptotic activity compared to either agent alone in a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 36343387).	36343387
BRAF V600E	colorectal cancer	sensitive	Panobinostat + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Farydak (panobinostat) synergistically inhibited cell viability and induced apoptosis in a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 36343387).	36343387
BRAF V600E	colorectal cancer	sensitive	Entinostat + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Entinostat (MS-275) resulted in greater apoptotic activity compared to either agent alone in a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 36343387).	36343387
BRAF V600E	colorectal cancer	sensitive	Trametinib + Valproic acid	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Valproic acid resulted in greater apoptotic activity compared to either agent alone in a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 36343387).	36343387
BRAF V600E	colorectal cancer	sensitive	Romidepsin + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Mekinist (trametinib) and Istodax (romidepsin) resulted in greater apoptotic activity compared to either agent alone in a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 36343387).	36343387
BRAF V600E	colorectal cancer	sensitive	Panobinostat + Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Zelboraf (vemurafenib) and Farydak (panobinostat) resulted in greater apoptotic activity compared to either agent alone in a colorectal cancer cell line harboring BRAF V600E in culture (PMID: 36343387).	36343387