BRAF gene as a potential target to attenuate drug resistance and treat cancer

In the year 2002, one of the breakthrough discoveries in the field of oncology was the identification of the BRAF mutation that leads to the development of BRAF inhibitors such as sorafenib, vemurafenib, dabrafenib and encorafenib. Paradoxical activation of the mitogen-activated protein kinase (MAPK) signaling pathway in conjunction with MAPK-independent parallel signaling networks such as PI3K/PTEN/AKT pathway failed single-agent BRAF inhibitors that prompted further research into combination therapy. Typically, BRAF mutated lung tumors are more aggressive and resistant to currently available therapies like chemotherapy and radiotherapy, but BRAF inhibitors have provided another effective tool for achieving a better non-small cell lung cancer (NSCLC) response rate with the advent of targeted drug therapy as monotherapy or in combination with MEK inhibitors. Combined MEK and BRAF inhibitors have been tested to induce apoptosis in BRAF V600 mutant melanoma cells to achieve complete pathway blockade, while BRAF inhibitors have shown promising clinical activity in BRAF mutant melanoma. However, monotherapy with BRAF inhibitor is ineffective in BRAF mutant colorectal cancer (CRC). The data from the relevant major therapeutic clinical trials have been addressed in this article with a detailed analysis of the mechanism of resistance and the future of BRAF inhibitors with advanced nanotechnology in the years to come.