BRAF inhibitors in cancer therapy.

Activating BRAF mutations, leading to constitutive activation of the MAPK signaling pathway, are common in a variety of human cancers. Several small molecule BRAF inhibitors have been developed during the last years and shown promising results in clinical trials, especially for metastatic melanoma, while they have been less effective in colon cancer. Two inhibitors, vemurafenib and dabrafenib, have been approved for treatment of melanoma. Unfortunately, in most patients who initially respond the tumors eventually develop acquired resistance to the BRAF inhibitors. So far, a number of resistance mechanisms have been identified, including secondary NRAS mutations and BRAF alternative splicing, leading to reactivation of the MAPK pathway. Other alterations, both upstream and downstream of BRAF can have the same effect, and activation of alternative pathways can also play a role in resistance to BRAF inhibitors. In addition, intra-tumor heterogeneity with the presence of clones of tumor cells lacking BRAF mutations needs to be considered, since wildtype BRAF can be activated by inhibitors designed to target mutated BRAF. Combination of the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib has significantly prolonged progression free survival compared to dabrafenib alone in metastatic melanoma. Combination treatments of BRAF inhibitors with other agents may not only circumvent or delay resistance, but may also lead to fewer side effects, such as development of secondary squamous tumors. Several clinical trials are underway for many different BRAF mutation positive cancers with BRAF inhibitors alone or in combination with other small molecule inhibitors, immunotherapies or conventional chemotherapy.