Adjuvant Fluorouracil, Leucovorin, and Oxaliplatin in Stage II to III Colon Cancer: Updated 10-Year Survival and Outcomes According to BRAF Mutation and Mismatch Repair Status of the MOSAIC Study.
The clinical studies in the manuscript by Al-Marrawi et al. describe the rational combination of signaling inhibitors in a colon cancer patient whose tumor cells express a mutant active B-RAFV600E protein that signals into the MEK1/2-ERK1/2 pathway downstream of K-RAS; this is a particularly aggressive form of colon cancer for which few rational therapeutic interventions have been available until recent times.
We determined the effects on clinical outcome of the BRAF mutation, microsatellite instability (MSI) and KRAS mutations in stage II and stage III colon carcinoma.
The kinetics of ctDNA derived from each cancer type were monitored targeting BRAFV600R (melanoma) and KRAS G13D (colon cancer), specifically reflected the status of the patient's tumours.
Here we investigated whether combination of 5-FU and a MEK inhibitor had treatment sequence-dependent synergistic effects in KRAS or BRAF mutant colon cancer models.
There was significant interaction in this association by BRAF mutation status (P = .03): smoking was associated with shorter DFS in patients with BRAF wild-type (HR, 1.36; 95% CI, 1.11 to 1.66) but not BRAF mutated (HR, 0.80; 95% CI, 0.50 to 1.29) colon cancer.
The CpG island methylator phenotype (CIMP-high, CIMP1) is a distinct phenotype associated with microsatellite instability (MSI) and BRAF mutation in colon cancer.
Relationships between adenomatous polyposis coli (APC) mutations, BRAFV600E mutations, and the CpG island methylator phenotype (CIMP) in colon cancer have not been explored.
BRAFV600E was associated with advanced TNM (P < 0.001), more distant metastases (P = 0.025), and worse overall survival (OS, P < 0.001; multivariate HR = 4.2, P = 0.004) in colon cancer patients.
A higher average number of mutations were observed in right versus left colorectal cancer (P < .01), with 13 of 14 BRAF mutations located in right colon cancer.
Conversely, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations were associated with colon cancer (13% vs 3%; P = .024) and older age (15.8% vs 4.6%; P = .006).
Here we report that colon cancer cells with mutant BRAF are also resistant to the heat shock protein 90 (HSP90) inhibitor AUY922, and that this is caused by rebound activation of ERK and Akt.
The subgroup of colon cancer (CRC) characterized by mutation in the BRAF gene and high mutation rate in the genomic DNA sequence, known as the microsatellite instability (MSI) phenotype, accounts for roughly 10% of the patients and derives from polyps with a serrated morphology.
Immunohistochemistry with Anti-BRAFV600E (VE1) Mouse Monoclonal Antibody is a Sensitive Method for Detection of the BRAFV600E Mutation in Colon Cancer: Evaluation of 120 Cases with and without KRAS Mutation and Literature Review.
In conclusion, our findings suggest that targeting ErbB-3 receptors could represent an effective therapeutic approach in BRAF-V600E mutant colon cancer.
Effect of MTH1 inhibition on tumour growth was explored in BRAFV600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models.