RAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase 
kinase) inhibitors are effective in treating patients with BRAF-mutant melanoma. 
However, most responses are partial and short-lived, and many patients fail to 
respond at all. We found that suppression of TORC1 activity in response to RAF 
or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein 
S6 (P-S6), effectively predicted induction of cell death by the inhibitor in 
BRAF-mutant melanoma cell lines. In resistant melanomas, TORC1 activity was 
maintained after treatment with RAF or MEK inhibitors, in some cases despite 
robust suppression of mitogen-activated protein kinase (MAPK) signaling. In in 
vivo mouse models, suppression of TORC1 after MAPK inhibition was necessary for 
induction of apoptosis and tumor response. Finally, in paired biopsies obtained 
from patients with BRAF-mutant melanoma before treatment and after initiation of 
RAF inhibitor therapy, P-S6 suppression predicted significantly improved 
progression-free survival. Such a change in P-S6 could be readily monitored in 
real time by serial fine-needle aspiration biopsies, making quantitation of P-S6 
a valuable biomarker to guide treatment in BRAF-mutant melanoma.