کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2151518 | 1089999 | 2011 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Identification of MET and SRC Activation in Melanoma Cell Lines Showing Primary Resistance to PLX4032
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کلمات کلیدی
v-raf murine sarcoma viral oncogene homolog B1p70S6KIGF1RMLPAMRP4Cyclin D1BRAFHGFTP53MITFBcrpCTNNB1CCND1CRAFv-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologmet proto-oncogene70-kDa ribosomal protein S6 kinasepTyrv-raf-1 murine leukemia viral oncogene homolog 1neuroblastoma RAS viral (v-ras) oncogene homologSTAT3SHCMALDI-TOFMMP-2NRASIC50FAKSRCERKMAPK - MAPKv-akt murine thymoma viral oncogene homolog - v-active ویروس آنفلوانزای ویروسی ویروسی tymomaAdenylate kinase - آدنیلات کینازAkt - آکتβ-catenin - بتا-کاتنینanalysis of variance - تحلیل واریانسANOVA - تحلیل واریانس Analysis of variancePhosphorylated tyrosine - تریروزین فسفریک شدهmultiplex ligation-dependent probe amplification - تقویت پروب وابسته چندگانهtumor protein p53 - تومور پروتئین p53Hepatocyte growth factor - عامل رشد هپاتوسیتMicrophthalmia-associated transcription factor - فاکتور رونویسی مرتبط با میکرو فتالمیphosphatase and tensin homolog - فسفاتاز و تنسین همولوگfluorescent in situ hybridization - فلورسنت در محل hybridizationmatrix metalloproteinase 2 - ماتریکس متالوپروتئیناز 2Fish - ماهیsignal transducer and activator of transcription 3 - مبدل سیگنال و فعال کننده رونویسی 3MEK - مجاهدین خلقMatrix-Assisted Laser Desorption/Ionization Time-of-Flight - مدت زمان پرواز یونیزاسیون لیزر ماتریکس کمک می کندMET - ملاقات کردbreast cancer resistance protein - پروتئین مقاومت به سرطان سینهMultidrug resistance protein 4 - پروتئین مقاومتی چندین رژیم 4mitogen-activated protein kinase - پروتئین کیناز فعال با mitogenPten - ژن PTENKit - کیتfocal adhesion kinase - کیناز چسبندگی کانونیinsulin-like growth factor 1 receptor - گیرنده فاکتور رشد 1 مانند انسولین
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
تحقیقات سرطان
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چکیده انگلیسی
PLX4032/vemurafenib is a first-in-class small-molecule BRAFV600E inhibitor with clinical activity in patients with BRAF mutant melanoma. Nevertheless, drug resistance develops in treated patients, and strategies to overcome primary and acquired resistance are required. To explore the molecular mechanisms involved in primary resistance to PLX4032, we investigated its effects on cell proliferation and signaling in a panel of 27 genetically characterized patient-derived melanoma cell lines. Cell sensitivity to PLX4032 was dependent on BRAFV600E and independent from other gene alterations that commonly occur in melanoma such as PTEN loss, BRAF, and MITF gene amplification. Two cell lines lacking sensitivity to PLX4032 and harboring a different set of genetic alterations were studied as models of primary resistance. Treatment with the MEK inhibitor UO126 but not with PLX4032 inhibited cell growth and ERK activation. Resistance to PLX4032 was maintained after CRAF down-regulation by siRNA indicating alternative activation of MEK-ERK signaling. Genetic characterization by multiplex ligation-dependent probe amplification and analysis of phosphotyrosine signaling by MALDI-TOF mass spectrometry analysis revealed the activation of MET and SRC signaling, associated with the amplification of MET and of CTNNB1 and CCND1 genes, respectively. The combination of PLX4032 with drugs or siRNA targeting MET was effective in inhibiting cell growth and reducing cell invasion and migration in melanoma cells with MET amplification; similar effects were observed after targeting SRC in the other cell line, indicating a role for MET and SRC signaling in primary resistance to PLX4032. Our results support the development of classification of melanoma in molecular subtypes for more effective therapies.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Neoplasia - Volume 13, Issue 12, December 2011, Pages 1132-1142, IN15-IN17
Journal: Neoplasia - Volume 13, Issue 12, December 2011, Pages 1132-1142, IN15-IN17
نویسندگان
Elisabetta Vergani, Viviana Vallacchi, Simona Frigerio, Paola Deho, Piera Mondellini, Paola Perego, Giuliana Cassinelli, Cinzia Lanzi, Maria Adele Testi, Licia Rivoltini, Italia Bongarzone, Monica Rodolfo,