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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.
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 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 + 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
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 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 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 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