A research team at Albert-Ludwigs-University in Germany led by Dr. Tilman Brummer studied the role of BRAF mutations in metastasis of colorectal carcinoma using a three-dimensional (3D) tissue culture model. The study entitled “B-Raf Inhibitors Induce Epithelial Differentiation in BRAF-Mutant Colorectal Cancer Cells” was published in the journal Cancer Research.
Colorectal carcinoma is the most frequent type of bowel cancer and the third most common cancer in both men and women in the United States. Mutations in the BRAF gene are associated with microsatellite stable colorectal cancer, an aggressive type of colorectal carcinoma. BRAF encodes a Ser/Thr kinase of the Ras/MEK/ERK pathway, which plays a crucial role in cell division. The most common mutation, V600E, occurs in 11% of colorectal carcinoma and renders the kinase constitutively active, inducing cell proliferation. The discovery of this mutation has pushed forward the development of drugs that inhibit kinase activity, such as vemurafenib or dabrafeni.
The research team analyzed the effect of BRAF inhibitors on the behavior of colorectal cancer cells in three-dimensional tissue culture, an experimental system that recapitulates many biological processes more reliably than conventional in vitro methods. As expected, the cell division rate of these cells was strongly reduced by BRAF inhibitors. Importantly, the researchers found that BRAF inhibitors not only reduce the division rate of cancer cells, but also induce their differentiation into cells with more mature features.
Namely, there was increased production of cell-cell adhesion molecules in drug-treated colorectal cancer cells. These molecules are located at the cell surface and maintain cells together, thereby decreasing the aggressive behavior of cancer cells so that they cannot break away from the primary tumor and initiate metastasis. In contrast, when the mutant BRAF (V600E) was introduced into colorectal cancer cells lacking the BRAF mutation, a more undifferentiated cell type was observed with a greater risk to metastasize.
The first clinical trials in colorectal cancer patients with BRAF inhibitors were not as promising as in melanoma treatment, though they were used individually. Based on these recent findings, combining BRAF inhibitors with other therapeutics might be more effective in colorectal cancer treatment. However, further investigation will be required to confirm this hypothesis.