Melanoma is an aggressive malignancy of melanocytes and most commonly arises in the skin.,In 2002, BRAF gene mutations were identified in melanoma, and this finding resulted in the development of several small-molecule molecular inhibitors that specifically targeted the BRAF V600E mutation.,The development of targeted therapies for advanced-stage melanoma, including tyrosine kinase inhibitors (TKIs) of the BRAF (V600E) kinase, vemurafenib and dabrafenib, have been approved for the treatment of advanced melanoma leading to improved clinical outcomes.,However, the development of BRAF inhibitor (BRAFi) resistance has significantly reduced the therapeutic efficacy after prolonged treatment.,Recent studies have identified the molecular mechanisms for BRAFi resistance.,This review aims to describe the impact of BRAFi resistance on the pathogenesis of melanoma, the current status of molecular pathways involved in BRAFi resistance, including intrinsic resistance, adaptive resistance, and acquired resistance.,This review will discuss how an understanding of the mechanisms associated with BRAFi resistance may aid the identification of useful strategies for overcoming the resistance to BRAF-targeted therapy in patients with advanced-stage melanoma.
The sustained clinical activity of the BRAF inhibitor vemurafenib (PLX4032/RG7204) in patients with BRAFV600 mutant melanoma is limited primarily by the development of acquired resistance leading to tumor progression.,Clinical trials are in progress using MEK inhibitors following disease progression in patients receiving BRAF inhibitors.,However, the PI3K/AKT pathway can also induce resistance to the inhibitors of MAPK pathway.,The sensitivity to vemurafenib or the MEK inhibitor AZD6244 was tested in sensitive and resistant human melanoma cell lines exploring differences in activation-associated phosphorylation levels of major signaling molecules, leading to the testing of co-inhibition of the AKT/mTOR pathway genetically and pharmacologically.,There was a high degree of cross-resistance to vemurafenib and AZD6244, except in two vemurafenib-resistant cell lines that acquired a secondary mutation in NRAS.,In other cell lines, acquired resistance to both drugs was associated with persistence or increase in activity of AKT pathway. siRNA-mediated gene silencing and combination therapy with an AKT inhibitor or rapamycin partially or completely reversed the resistance.,Primary and acquired resistance to vemurafenib in these in vitro models results in frequent cross resistance to MEK inhibitors, except when the resistance is the result of a secondary NRAS mutation.,Resistance to BRAF or MEK inhibitors is associated with the induction or persistence of activity within the AKT pathway in the presence of these drugs.,This resistance can be potentially reversed by the combination of a RAF or MEK inhibitor with an AKT or mTOR inhibitor.,These combinations should be available for clinical testing in patients progressing on BRAF inhibitors.