title: Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma.
abstract: PURPOSE To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAF(V600)-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. METHODS In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1(P124) coexisting with BRAF(V600) were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRAS(Q61) mutations or MEK1(Q56P) or MEK1(E203K) mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. CONCLUSION Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.
authors.affiliation: Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232-6307, USA. jeff.sosman@vanderbilt.edu
authors.forename: Kerstin
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authors.lastname: Trunzer
authors.forename: Anna C
authors.initials: AC
authors.lastname: Pavlick
authors.forename: Lynn
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authors.lastname: Schuchter
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
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authors.initials: GA
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authors.forename: Thomas E
authors.initials: TE
authors.lastname: Hutson
authors.forename: Stergios J
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authors.lastname: Moschos
authors.forename: Keith T
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authors.lastname: Flaherty
authors.forename: Kevin B
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authors.lastname: Kim
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Weber
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.forename: Donald
authors.initials: D
authors.lastname: Lawrence
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Ott
authors.forename: Ravi K
authors.initials: RK
authors.lastname: Amaravadi
authors.forename: Karl D
authors.initials: KD
authors.lastname: Lewis
authors.forename: Igor
authors.initials: I
authors.lastname: Puzanov
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.forename: Astrid
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authors.lastname: Koehler
authors.forename: Mark
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authors.lastname: Kockx
authors.forename: Olivia
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authors.lastname: Spleiss
authors.forename: Annette
authors.initials: A
authors.lastname: Schell-Steven
authors.forename: Houston N
authors.initials: HN
authors.lastname: Gilbert
authors.forename: Louise
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authors.lastname: Cockey
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lee
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Joe
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sosman
authors.forename: Antoni
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authors.lastname: Ribas
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1 / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D008565:Membrane Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human