ORCID Profile
0000-0002-1357-4666
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Publisher: American Association for Cancer Research (AACR)
Date: 07-11-2023
DOI: 10.1158/1535-7163.MCT-22-0101
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.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523091
Abstract: Supplementary figure 4 shows phosphorylated ERK staining in an adenoma from a ACDX2 mouse
Publisher: Springer Science and Business Media LLC
Date: 23-05-2022
DOI: 10.1038/S41418-022-01016-W
Abstract: Colorectal cancers (CRCs) often display histological features indicative of aberrant differentiation but the molecular underpinnings of this trait and whether it directly drives disease progression is unclear. Here, we identify co-ordinate epigenetic inactivation of two epithelial-specific transcription factors, EHF and CDX1, as a mechanism driving differentiation loss in CRCs. Re-expression of EHF and CDX1 in poorly-differentiated CRC cells induced extensive chromatin remodelling, transcriptional re-programming, and differentiation along the enterocytic lineage, leading to reduced growth and metastasis. Strikingly, EHF and CDX1 were also able to reprogramme non-colonic epithelial cells to express colonic differentiation markers. By contrast, inactivation of EHF and CDX1 in well-differentiated CRC cells triggered tumour de-differentiation. Mechanistically, we demonstrate that EHF physically interacts with CDX1 via its PNT domain, and that these transcription factors co-operatively drive transcription of the colonic differentiation marker, VIL1 . Compound genetic deletion of Ehf and Cdx1 in the mouse colon disrupted normal colonic differentiation and significantly enhanced colorectal tumour progression. These findings thus reveal a novel mechanism driving epithelial de-differentiation and tumour progression in CRC.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523088.V1
Abstract: Supplementary figure 5 shows mouse weight during treatment in two of the mouse studies
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523100.V1
Abstract: Supplementary figure 2 shows the effect of trametinib plus panobinostat on colony formation in HCT 116 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523085.V1
Abstract: Supplementary table 1
Publisher: Informa UK Limited
Date: 20-02-2014
DOI: 10.4161/CBT.28179
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523094.V1
Abstract: Supplementary figure 3 shows combining trametinib with different classes of HDAC inhibitors in COLO 201 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523103.V1
Abstract: Supplementary Figure 1 shows the synergistic effect of trametinib plus panobinostat in CRC cell lines and PDTO's
Publisher: Springer Science and Business Media LLC
Date: 22-11-2019
DOI: 10.1038/S41467-019-13180-8
Abstract: Histone deacetylase 3 ( Hdac3 ) regulates the expression of lipid metabolism genes in multiple tissues, however its role in regulating lipid metabolism in the intestinal epithelium is unknown. Here we demonstrate that intestine-specific deletion of Hdac3 ( Hdac3 IKO ) protects mice from diet induced obesity. Intestinal epithelial cells (IECs) from Hdac3 IKO mice display co-ordinate induction of genes and proteins involved in mitochondrial and peroxisomal β-oxidation, have an increased rate of fatty acid oxidation, and undergo marked remodelling of their lipidome, particularly a reduction in long chain triglycerides. Many HDAC3-regulated fatty oxidation genes are transcriptional targets of the PPAR family of nuclear receptors, Hdac3 deletion enhances their induction by PPAR-agonists, and pharmacological HDAC3 inhibition induces their expression in enterocytes. These findings establish a central role for HDAC3 in co-ordinating PPAR-regulated lipid oxidation in the intestinal epithelium, and identify intestinal HDAC3 as a potential therapeutic target for preventing obesity and related diseases.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523100
Abstract: Supplementary figure 2 shows the effect of trametinib plus panobinostat on colony formation in HCT 116 cells
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523103
Abstract: Supplementary Figure 1 shows the synergistic effect of trametinib plus panobinostat in CRC cell lines and PDTO's
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.C.6543591.V1
Abstract: 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 i in vitro /i , and attenuated i Apc /i -initiated adenoma formation i in vivo /i . 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, KRAS sup G12C /sup or BRAF sup V600 /sup inhibitor in i KRAS/BRAF sup WT /sup /i i KRAS sup G12C /sup /i , i BRAF sup V600E /sup /i 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. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.C.6543591
Abstract: 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 i in vitro /i , and attenuated i Apc /i -initiated adenoma formation i in vivo /i . 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, KRAS sup G12C /sup or BRAF sup V600 /sup inhibitor in i KRAS/BRAF sup WT /sup /i i KRAS sup G12C /sup /i , i BRAF sup V600E /sup /i 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. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523085
Abstract: Supplementary table 1
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523088
Abstract: Supplementary figure 5 shows mouse weight during treatment in two of the mouse studies
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1535-7163.22523091.V1
Abstract: Supplementary figure 4 shows phosphorylated ERK staining in an adenoma from a ACDX2 mouse
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1535-7163.22523094
Abstract: Supplementary figure 3 shows combining trametinib with different classes of HDAC inhibitors in COLO 201 cells
No related grants have been discovered for Irvin Ng.