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Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death
journal contribution
posted on 2023-02-20, 22:53 authored by LJ Jenkins, IY Luk, WD Fairlie, EF Lee, M Palmieri, KL Schoffer, T Tan, I Ng, N Vukelic, S Tran, JWT Tse, R Nightingale, Z Alam, F Chionh, G Iatropoulos, M Ernst, S Afshar-Sterle, J Desai, P Gibbs, OM Sieber, Amardeep DhillonAmardeep Dhillon, NC Tebbutt, JM MariadasonThe 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.
History
Journal
Molecular cancer therapeuticsVolume
22Pagination
52-62Location
United StatesPublisher DOI
ISSN
1535-7163eISSN
1538-8514Language
EnglishPublication classification
C1 Refereed article in a scholarly journalIssue
1Publisher
AMER ASSOC CANCER RESEARCHUsage metrics
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Keywords
Science & TechnologyLife Sciences & BiomedicineOncologyHISTONE DEACETYLASE INHIBITORSRECEPTOR MONOCLONAL-ANTIBODYSIGNALING PATHWAYAMG 510PHOSPHORYLATIONEXPRESSIONACTIVATIONPROMOTESPROTEINCOLONHumansApoptosisApoptosis Regulatory ProteinsCell DeathCell Line, TumorColorectal NeoplasmsErbB ReceptorsHistone Deacetylase InhibitorsMitogen-Activated Protein Kinase KinasesMAP Kinase Signaling SystemDigestive DiseasesClinical ResearchCancerColo-Rectal CancerRare Diseases5.1 Pharmaceuticals5 Development of treatments and therapeutic interventionsPharmacology and Pharmaceutical Sciences not elsewhere classifiedOncology and Carcinogenesis not elsewhere classified
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