Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.7.12.2 (
MEK
)
18,161
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The targeting of activated epidermal growth factor receptor (EGFR) with therapeutic anti-EGFR monoclonal antibodies (mAbs) such as cetuximab and panitumumab has been used as an effective strategy in the treatment of colorectal cancer (CRC). However, its clinical efficacy occurs only in a limited number of patients. Here, we performed whole-transcriptome analysis in xenograft mouse tumors induced by
KRAS
G12D
mutation-bearing LS174T CRC cells following treatment with either cetuximab or PBS. Through integrated analyses of differential gene expression with TCGA and CCLE public database, we identified
TNS4
, overexpressed in CRC patients and
KRAS
mutation-harboring CRC cell lines, significantly downregulated by cetuximab. While ablation of
TNS4
expression via shRNA results in significant growth inhibition of LS174T, DLD1, WiDr, and DiFi CRC cell lines, conversely, its ectopic expression increases the oncogenic growth of these cells. Furthermore,
TNS4
expression is transcriptionally regulated by MAP kinase signaling pathway. Consistent with this finding, selumetinib, a
MEK1
/2 inhibitor, suppressed oncogenic activity of CRC cells, and this effect is more profound in combination with cetuximab. Altogether, we propose that
TNS4
plays a crucial role in CRC tumorigenesis, and that suppression of
TNS4
would be an effective therapeutic strategy in treating a subset of cetuximab-refractory CRC patients including
KRAS
activating mutations.
...
PMID:Whole Transcriptome Analysis Identifies TNS4 as a Key Effector of Cetuximab and a Regulator of the Oncogenic Activity of KRAS Mutant Colorectal Cancer Cell Lines. 3140 52
