کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2151859 | 1090028 | 2010 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Pharmacodynamic Characterization of the Efficacy Signals Due to Selective BRAF Inhibition with PLX4032 in Malignant Melanoma
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کلمات کلیدی
Dmgv-raf murine sarcoma viral oncogene homolog B1MITFCTNNB1RTKEDNRBBRAFMc1rendothelin receptor type BcKitETVATCCHMXNPGNRAS mutationPTEN mutationneuroblastoma RAS viral (v-ras) oncogene homologFOSL1SCPERKNCCPI3KmTORSchwann cell precursorNRASMYCv-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologDUSP - DusperMAPK - MAPKMAPK/ERK kinase - MAPK / ERK kinaseSOx - SOXv-akt murine thymoma viral oncogene homolog - v-active ویروس آنفلوانزای ویروسی ویروسی tymomaAkt - آکتβ-catenin - بتا-کاتنینanalysis of variance - تحلیل واریانسANOVA - تحلیل واریانس Analysis of varianceTyr - تیرRTK, Receptor tyrosine kinase - تیروزین کینازهای گیرنده ایTyrosinase - تیروزیناز BRAF mutation - جهش BRAFneural crest cell - سلول های خونی عصبیMicrophthalmia-associated transcription factor - فاکتور رونویسی مرتبط با میکرو فتالمیphosphatase and tensin homolog - فسفاتاز و تنسین همولوگphosphoinositide-3-kinase - فسفونیوییدید-3-کینازMetallothioneins - متالوتیژیونMEK - مجاهدین خلقAmerican Type Culture Collection - مجموعه فرهنگی نوع آمریکاییmalignant melanoma - ملانوم بدخیمMechanistic target of rapamycin - هدف مکانیکی رپامایسینmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenPten - ژن PTENSpry - کشیدنextracellular signal-regulated kinase - کیناز تنظیم شده سیگنال خارج سلولیMelanocortin 1 receptor - گیرنده ملانوکورتین 1
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
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چکیده انگلیسی
PURPOSE: About 65% to 70% of melanomas harbor a mutation in v-raf murine sarcoma viral oncogene homolog B1 (BRAF) that causes the steady-state activation of extracellular signal-regulated kinase (ERK). We sought to investigate the efficacy of PLX4032 (BRAF inhibitor) to identify patterns/predictors of response/resistance and to study the effects of BRAF in melanoma. EXPERIMENTAL DESIGN: Well-characterized melanoma cell lines, including several with acquired drug resistance, were exposed to PLX4032. Growth inhibition, phosphosignaling, cell cycle, apoptosis, and gene expression analyses were performed before and after exposure to drug. RESULTS: Using a growth-adjusted inhibitory concentration of 50% cutoff of 1 µM, 13 of 35 cell lines were sensitive to PLX4032, 16 resistant, and 6 intermediate (37%, 46%, and 17% respectively). PLX4032 caused growth inhibition, G0/G1 arrest, and restored apoptosis in the sensitive cell lines. A BRAF mutation predicted for but did not guarantee a response, whereas a neuroblastoma RAS viral oncogene homolog mutation or wild-type BRAF conferred resistance. Cells with concurrent BRAF mutations and melanocortin 1 receptor germ line variants and/or a more differentiated melanocyte genotype had a preferential response. Acquired PLX4032 resistance reestablishes ERK signaling, promotes a nonmelanocytic genotype, and is associated with an increase in the gene expression of certain metallothioneins and mediators of angiogenesis. CONCLUSIONS: PLX4032 has robust activity in BRAF mutated melanoma. The preclinical use of this molecule identifies criteria for its proper clinical application, describes patterns of and reasons for response/resistance, and affords insight into the role of a BRAF mutation in melanoma.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neoplasia - Volume 12, Issue 8, August 2010, Pages 637-649, IN3
Journal: Neoplasia - Volume 12, Issue 8, August 2010, Pages 637-649, IN3
نویسندگان
William D. Tap, Ke-Wei Gong, Judy Daring, Yiou Tseng, Charles Ginther, Giovanni Pauletti, John A. Glaspy, Richard Essner, Gideon Bollag, Peter Hirth, Chao Zhang, Dennis J. Slamon,