Identification and Characterization of Small-Molecule Inhibitors to Selectively Target the DFG-in over the DFG-out Conformation of the B-Raf Kinase V600E Mutant in Colorectal Cancer.
Thus, large-scale KRAS mutation screening is needed for efficient patient management and in the future metastatic colorectal cancer genotyping might also include the detection of the BRAF V600E mutation, which is a very strong negative prognostic factor in colorectal cancer.
In protein extracts (2 mg) from 11 CRC tissue specimens, the MRM assay could measure WT BRAF in all 11 cases (0.32-1.66 ng) and the V600E BRAF in two cases (0.1-0.13 ng; mutant-to-WT ratio, 0.16-0.17).
The current data showed instead that the BRAF V599E mut</span>ation was associated only with a subgroup of colorectal carcinomas with MSI that were obtained from older patients without hereditary nonpolyposis colorectal carcinoma and showed epigenetic silencing of hMLH1.
We conclude that a single endogenous BRAF(V600E) allele is sufficient to repress BIM and prevent death arising from growth factor withdrawal, and CRC cells with BRAF(V600E) mutations are addicted to the ERK1/2 pathway for repression of BIM and growth factor-independent survival.
The FDA-approved anti-helminthic drug rafoxanide was recently reported to antagonize the oncogenic function of the BRAF V600E mutant protein, commonly found in CRCs, as well as to inhibit the proliferation of skin cancer cells.
We have prospectively studied a series of 1624 consecutive colorectal carcinomas with an algorithm including immunohistochemical analysis of mismatch repair proteins and molecular study of microsatellite instability and BRAF c.1799 T > A (p.V600E) gene mutations.
BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF-mutated cases.
These results seem to indicate that Cdx2 may play a role in the serrated pathway to colorectal cancer as underlined by strong relationships with BRAF(V600E), CIMP-high and MMR-deficiency.
Previous studies have reported that rafoxanide, as an inhibitor of BRAF V600E mutant protein, inhibits the growth of colorectal cancer, multiple myeloma, and skin cancer.
The aim of this study was to compare the association of BRAF V600E mutation in interval versus non-interval colorectal cancers and to determine the relationship between BRAF mutation and 5-year survival.
Approximately 5-10% of metastatic colorectal cancers harbor a BRAF-V600E mutation, which is correlated with resistance to EGFR-targeted therapies and worse clinical outcome.
BRAF V600E mutation was found in 15.6% of colorectal cancers but at higher frequencies in cancers with proximal location, poor differentiation and microsatellite instability (MSI) (all p < 0.001).
The aim of this study was to relate the CpG island methylator phenotype (CIMP; characterized by extensive promoter hypermethylation) to cancer-specific survival in colorectal cancer, taking into consideration relevant clinicopathologic factors, such as microsatellite instability (MSI) screening status and the BRAF V600E mutation.