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Drugs that inhibit RAF/MEK signaling, such as vemurafenib, elicit profound but often temporary anti-tumor responses in patients with BRAF(V) (600E) melanoma. Adaptive responses to RAF/MEK inhibition occur on a timescale of hours to days, involve homeostatic responses that reactivate MAP kinase signaling and compensatory mitogenic pathways, and attenuate the anti-tumor effects of RAF/MEK inhibitors. We profile adaptive responses across a panel of melanoma cell lines using multiplex biochemical measurement, single-cell assays, and statistical modeling and show that adaptation involves at least six signaling cascades that act to reduce drug potency (IC50) and maximal effect (i.e., Emax ≪ 1). Among these cascades, we identify a role for JNK/c-Jun signaling in vemurafenib adaptation and show that RAF and JNK inhibitors synergize in cell killing. This arises because JNK inhibition prevents a subset of cells in a cycling population from becoming quiescent upon vemurafenib treatment, thereby reducing drug Emax. Our findings demonstrate the breadth and diversity of adaptive responses to RAF/MEK inhibition and a means to identify which steps in a signaling cascade are most predictive of phenotypic response.
Pubmed ID: 25814555 RIS Download
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This monoclonal targets JUND
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View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsThis polyclonal targets Cleaved PARP (Asp214) (Human Specific)
View all literature mentionsThis monoclonal targets NF-KappaB p65, phospho (Ser536)
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
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View all literature mentionsThis polyclonal targets Phospho-SAPK/JNK (Thr183/Tyr185)
View all literature mentionsThis monoclonal targets Phospho-Stat3 (Tyr705)
View all literature mentionsThis monoclonal targets Phospho-HSP27 (Ser82) (D1H2) XP Rabbit mAb
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
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View all literature mentionsThis monoclonal targets Genetic locus: RELA (human) mapping to 11q13.1; Rela (mouse) mapping to 19 A.
View all literature mentionsThis polyclonal targets p-Rb (Ser 807/811)
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View all literature mentionsThis monoclonal targets 4E-BP1, phospho (Thr37 / Thr46)
View all literature mentionsThis monoclonal targets Phospho-c-Jun (Ser73)
View all literature mentionsThis polyclonal targets Rabbit IgG (H+L)
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View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets Human c-Jun, phospho (Ser63)
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View all literature mentionsThis monoclonal targets Mapk14
View all literature mentionsThis monoclonal targets AMPK-alpha, phospho (Thr172)
View all literature mentionsThis polyclonal targets Phospho-p70 S6 Kinase (Thr389)
View all literature mentionsThis polyclonal targets Phospho-p90RSK (Thr573)
View all literature mentionsThis unknown targets p90RSK, phospho (Ser380)
View all literature mentionsThis monoclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsSystem control software used for data acquisition and analysis for microarray images.
View all literature mentionsAutomated software program for image analysis based on microarray based image application. Various output styles are available, including image overlay with warping and registration and scattered correlation plot with 2D or 3D spot profile. Outputs can be formatted in text, xml, excel, or custom format.
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis unknown targets Goat IgG (H+L)
View all literature mentionsThis monoclonal targets Genetic locus: RELA (human) mapping to 11q13.1; Rela (mouse) mapping to 19 A.
View all literature mentionsThis polyclonal targets p-Rb (Ser 807/811)
View all literature mentionsThis monoclonal targets Phospho-Stat3 (Tyr705)
View all literature mentionsThis monoclonal targets c-Jun
View all literature mentionsThis monoclonal targets 4E-BP1, phospho (Thr37 / Thr46)
View all literature mentionsThis monoclonal targets Phospho-c-Jun (Ser73)
View all literature mentionsThis polyclonal targets Rabbit IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis monoclonal targets Human Bim
View all literature mentionsThis monoclonal targets Human c-Jun, phospho (Ser63)
View all literature mentionsThis monoclonal targets Cdkn1b
View all literature mentionsThis monoclonal targets Histone H3, phospho (Ser10)
View all literature mentionsThis monoclonal targets Mapk14
View all literature mentionsThis monoclonal targets AMPK-alpha, phospho (Thr172)
View all literature mentionsThis polyclonal targets Phospho-p70 S6 Kinase (Thr389)
View all literature mentionsThis polyclonal targets Phospho-p90RSK (Thr573)
View all literature mentionsThis unknown targets p90RSK, phospho (Ser380)
View all literature mentionsThis monoclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsThis polyclonal targets Cleaved PARP (Asp214) (Human Specific)
View all literature mentionsThis monoclonal targets Phospho-HSP27 (Ser82) (D1H2) XP Rabbit mAb
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets JUND
View all literature mentionsThis polyclonal targets Phospho-SAPK/JNK (Thr183/Tyr185)
View all literature mentionsThis monoclonal targets NF-KappaB p65, phospho (Ser536)
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-mTOR (Ser2448)
View all literature mentionsThis polyclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis polyclonal targets
View all literature mentionsThis polyclonal targets Phospho-mTOR (Ser2448)
View all literature mentionsThis monoclonal targets NF-KappaB p65, phospho (Ser536)
View all literature mentionsThis monoclonal targets Phospho-HSP27 (Ser82) (D1H2) XP Rabbit mAb
View all literature mentionsThis polyclonal targets Cleaved PARP (Asp214) (Human Specific)
View all literature mentionsThis polyclonal targets Phospho-SAPK/JNK (Thr183/Tyr185)
View all literature mentionsThis monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb
View all literature mentionsThis monoclonal targets Phospho-Akt (Ser473)
View all literature mentionsThis monoclonal targets JUND
View all literature mentionsThis polyclonal targets
View all literature mentionsThis monoclonal targets Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204)
View all literature mentionsThis polyclonal targets Phospho-Akt (Ser473)
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