ORCID Profile
0000-0002-7000-5806
Current Organisations
South West Healthcare
,
Olivia Newton-John Cancer Centre at Austin Health
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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: 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: 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: 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.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: 10.1158/1535-7163.22523103
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: 10.1158/1535-7163.22523085
Abstract: Supplementary table 1
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: 10.1158/1535-7163.22523088
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: 10.1158/1535-7163.22523094
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: 04-2023
DOI: 10.1158/1535-7163.22523091.V1
Abstract: Supplementary figure 4 shows phosphorylated ERK staining in an adenoma from a ACDX2 mouse
Location: Australia
No related grants have been discovered for George Iatropoulos.