AI Article Synopsis
- KRAS is a crucial gene in colorectal cancer but is difficult to target with drugs, leading researchers to focus on inhibiting signaling pathways like RAF/MEK/ERK and PI3K/Akt instead.
- Despite extensive clinical trials, drugs targeting these pathways have not been successful, prompting further investigation into their activity in tumors.
- Surprisingly, most colorectal tumors showed lower levels of activated ERK and Akt compared to normal tissue, even though a majority had increased SOX9 levels, suggesting these signaling pathways may not be active in most cases of colorectal cancer.
Article Abstract
KRAS is a gatekeeper gene in human colorectal tumorigenesis. KRAS is 'undruggable'; hence, efforts have been diverted to inhibit downstream RAF/MEK/ERK and PI3K/Akt signaling. Nevertheless, none of these inhibitors has progressed to clinical use despite extensive trials. We examined levels of phospho-ERK1/2(T202/Y204) and phospho-Akt1/2/3(S473) in human colorectal tumor compared to matched mucosa with semi-quantitative near-infrared western blot and confocal fluorescence immunohistochemistry imaging. Surprisingly, 75.5% (25/33) of tumors had lower or equivalent phospho-ERK1/2 and 96.9% (31/32) of tumors had lower phospho-Akt1/2/3 compared to matched mucosa, irrespective of KRAS mutation status. In contrast, we discovered KRAS-dependent SOX9 upregulation in 28 of the 31 (90.3%) tumors. These observations were substantiated by analysis of the public domain transcriptomics The Cancer Genome Atlas (TCGA) and NCBI Gene Expression Omnibus (GEO) datasets and proteomics Clinical Proteomic Tumor Analysis Consortium (CPTAC) dataset. These data suggest that RAF/MEK/ERK and PI3K/Akt signaling are unlikely to be activated in most human colorectal cancer.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8895447 | PMC |
| http://dx.doi.org/10.1002/1878-0261.13163 | DOI Listing |
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