BACKGROUND: The sustained clinical activity of the BRAF inhibitor vemurafenib 
(PLX4032/RG7204) in patients with BRAF(V600) 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.
METHODOLOGY/PRINCIPAL FINDINGS: 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.
CONCLUSIONS/SIGNIFICANCE: 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.