Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line, Tumor
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Down-Regulation / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Indoles / pharmacology
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Indoles / therapeutic use
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Mechanistic Target of Rapamycin Complex 1
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Melanoma / drug therapy
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Melanoma / enzymology*
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Melanoma / genetics*
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Melanoma / pathology
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Mice
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Multiprotein Complexes / antagonists & inhibitors*
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Multiprotein Complexes / metabolism
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Mutation / genetics*
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Ribosomal Protein S6 / metabolism
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use
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TOR Serine-Threonine Kinases / antagonists & inhibitors*
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TOR Serine-Threonine Kinases / metabolism
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Vemurafenib
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Xenograft Model Antitumor Assays
Substances
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Indoles
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Multiprotein Complexes
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Protein Kinase Inhibitors
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Ribosomal Protein S6
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Sulfonamides
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Vemurafenib
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BRAF protein, human
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Mechanistic Target of Rapamycin Complex 1
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Proto-Oncogene Proteins B-raf
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TOR Serine-Threonine Kinases
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Extracellular Signal-Regulated MAP Kinases
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Mitogen-Activated Protein Kinase Kinases