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.