Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/31954
Title: Genotype-Tailored ERK/MAPK Pathway and HDAC Inhibition Rewires the Apoptotic Rheostat to Trigger Colorectal Cancer Cell Death.
Austin Authors: Jenkins, Laura J;Luk, Ian Y;Fairlie, Walter Douglas ;Lee, Erinna F;Palmieri, Michelle;Schoffer, Kael L;Tan, Tao;Ng, Irvin;Vukelic, Natalia;Tran, Sharon;Tse, Janson W T;Nightingale, Rebecca;Alam, Zakia;Chionh, Fiona;Iatropoulos, George F ;Ernst, Matthias ;Afshar-Sterle, Shoukat ;Desai, Jayesh;Gibbs, Peter;Sieber, Oliver M;Dhillon, Amardeep S ;Tebbutt, Niall C ;Mariadason, John M 
Affiliation: Olivia Newton-John Cancer Research Institute
Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
Issue Date: 3-Jan-2023
Publication information: Molecular cancer therapeutics 2023; 22(1): 52-62
Abstract: 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/31954
DOI: 10.1158/1535-7163.MCT-22-0101
ORCID: 0000-0001-9218-8669
0000-0001-7229-0543
0000-0002-2498-1160
0000-0003-1255-9808
0000-0003-3379-9974
0000-0002-5683-9935
0000-0001-5924-4112
0000-0002-1357-4666
0000-0003-0123-5701
0000-0003-1321-5556
0000-0002-4592-1220
0000-0003-3251-4113
0000-0002-9426-4538
0000-0002-9392-5816
0000-0002-7000-5806
0000-0002-6399-1177
0000-0003-2678-7297
0000-0003-4246-9344
0000-0003-1423-4484
0000-0001-9480-0786
0000-0002-6065-663X
0000-0003-2613-5168
0000-0001-9123-7684
Journal: Molecular cancer therapeutics
Start page: 52
End page: 62
PubMed URL: 36343387
ISSN: 1538-8514
Type: Journal Article
Subjects: Colorectal Neoplasms/drug therapy
Colorectal Neoplasms/genetics
Colorectal Neoplasms/metabolism
Histone Deacetylase Inhibitors/pharmacology
Appears in Collections:Journal articles

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