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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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