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Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas.

ABSTRACT: Analysis of transcriptome kinetics of SW1736 thyroid cancer cell line vs SK-MEL-28 melanoma cell line at various times after addition of 2 µM vemurafenib. The hypothesis tested was that SW1736 cells (vemurafenib-refractory) differentially express genes compared to SK-MEL-28 cells (vemurafenib sensitive) that confer resistance to the RAF inhibitor. Total RNA was obtained from lysates of SW1726 and SK-MEL-28 cells treated with 2 µM vemurafenib for 0, 1, 6 and 48 h. Experiment was made by triplicate.

ORGANISM(S): Homo sapiens

SUBMITTER: Cristina Montero-Conde

PROVIDER: E-GEOD-37441 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF-mutant thyroid carcinomas.

Montero-Conde Cristina C Ruiz-Llorente Sergio S Dominguez Jose M JM Knauf Jeffrey A JA Viale Agnes A Sherman Eric J EJ Ryder Mabel M Ghossein Ronald A RA Rosen Neal N Fagin James A JA

Cancer discovery 20130129 5

The RAF inhibitor vemurafenib (PLX4032) increases survival in patients with BRAF-mutant metastatic melanoma, but has limited efficacy in patients with colorectal cancers. Thyroid cancer cells are also comparatively refractory to RAF inhibitors. In contrast to melanomas, inhibition of mitogen-activated protein kinase (MAPK) signaling by PLX4032 is transient in thyroid and colorectal cancer cells. The rebound in extracellular signal-regulated kinase (ERK) in thyroid cells is accompanied by increas ...[more]

PMID: 23365119

Similar Datasets

Relief of feedback inhibition of HER3 transcription by RAF and MEK inhibitors attenuates their antitumor effects in BRAF mutant thyroid carcinomas.

Project description:Analysis of transcriptome kinetics of SW1736 thyroid cancer cell line vs SK-MEL-28 melanoma cell line at various times after addition of 2 µM vemurafenib. The hypothesis tested was that SW1736 cells (vemurafenib-refractory) differentially express genes compared to SK-MEL-28 cells (vemurafenib sensitive) that confer resistance to the RAF inhibitor.

2013-02-01 | GSE37441 | GEO

RNA-Sequencing of vemurafenib-sensitive and resistant melanoma cell line SKMEL-239

Project description:RNA-seq data were generated for two conditions: for parental SK-MEL-239 cells grown in normal media and resistant SK-MEL-239 cells grown in media supplemented with vemurafenib.

2022-04-16 | E-MTAB-11609 | biostudies-arrayexpress

RNA-seq of MYC-inducible SK-MEL-28 cells

Project description:MYC-inducible SK-MEL-28 cells with or without MYC-induction were analyzed

2018-05-01 | GSE101541 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of ADORA1 knockdown and scrambled-shRNA control cells' Transcriptomes

Project description:Expression profiles of ADORA1-shRNA-transfected Sk-mel-28 human melanoma cell line and scrambled-shRNA control cells

2020-07-23 | GSE134493 | GEO

MKK2 is sufficient but not necessary for proliferation and anchorage-independent growth of SK-MEL-28 cells.

Project description:Though mitogen activated protein kinase kinases (MKK or MEK) 1 and 2 are widely assumed to be functionally redundant some reports indicate they possess distinct biologic activities. To test the hypothesis that MEK1 and MEK2 signaling pathways are interchangeable we used two complementary approaches to determine the necessity and sufficiency of individual MEK1 and MEK2 signaling pathways for human melanoma SK-MEL-28 cell proliferation. To test the necessity we targeted MEK1 and/or MEK2 using specific siRNAs. An effect on proliferation was observed only when both MEK1 and MEK2 were knocked down indicating that neither of the individual MEK isoforms is necessary for SK-MEL-28 cell proliferation. To test the sufficiency we inhibited multiple MEK and MKK signaling pathways in SK-MEL-28 cells with anthrax lethal toxin (LeTx) a MEK/MKK-specific protease and rescued individual MEK signaling pathways by expressing a cleavage-resistant form of MEK (MEKcr). In this fashion ERK activation was retained only in MEK2cr-expressing cells but not in MEK1cr-expressing cells following LeTx treatment. Microarray analysis revealed groups of non-overlapping downstream transcriptional targets of MEK1 and MEK2 and indicated a substantial rescue effect of MEK2cr on proliferation pathways. Furthermore LeTx efficiently inhibited the cell proliferation and anchorage-independent growth of SK-MEL-28 cells expressing MKK1cr but not MEK2cr. These results not only indicate that in this cellular context MEK2 signaling pathway alone is sufficient for ERK activation melanoma cell proliferation and anchorage-independent growth but MEK1 is not but also demonstrate that MEK1 and MEK2 signaling pathways are not redundant and interchangeable for melanoma cell proliferation. We conclude that while MEK2 alone is sufficient for SK-MEL-28 cell proliferation MEK1 can conditionally compensate for loss of MEK2. SK-MEL-28 melanoma cells +/- cleavage resistant MKK1/MKK2

2011-06-24 | E-GEOD-23930 | biostudies-arrayexpress

Identification of TFAP2A and MITF binding sites in the melanoma cell line SK-MEL-28

Project description:TFAP2A and MITF binding sites were identified in SK-MEL-28 cell lines using Cleavage Under Targets and Release Using Nuclease (CUT&RUN).

2021-02-08 | GSE153020 | GEO

A novel RAF kinase inhibitor with DFG-out binding mode: high efficacy in BRAF-mutant tumor xenograft models in the absence of normal tissue hyperproliferation

Project description:Purpose: Seek for differential gene expression in vemurafenib-resistant A375 tumors vs. untreated controls to provide a rationale for resistance mechanism Methods: mRNA profiles of vemurafenib-resistant A375 tumors and untreated control tumors were generated by transcriptome sequencing of A375 melanoma bearing mice. Since our xenograft samples contain a mixture of human and mouse RNAs we mapped RNASeq reads against a hybrid human/mouse genome. We than removed reads of potential mouse origin by taking only reads that map uniquely to human chromosomes. On average 23% of reads were removed as potential mouse reads. We than took the remaining reads (on average 77% per sample) to determine the gene expression levels for each sample. Normalized expression levels of 5 resistant samples were compared to 4 untreated control samples to detect differnetially regulated genes which may contribute to vemurfenib resistance Results: Expression levels of several genes were consistently altered in all resistant samples. Expression of e.g. genes encoding SPRY2, SPRY4, DUSP6, CCND1, PIK3R3, FGFR1, EPHA4, MCL1, and IGF1R was down-regulated, whereas expression of PDGFC, VEGFC, ABCB9 and KITLG was increased. Conclusions: Our study reports several differentially expressed genes which may contribute to vemurafenib resistance in A375 tumor bearing mice RNA sequencing of genes expressed in A375 tumors bearing mice treated with vemurafenib until in vivo resistance appeared vs. untreated A375 tumors

2016-07-03 | E-GEOD-74729 | biostudies-arrayexpress

MKK2 is sufficient but not necessary for proliferation and anchorage-independent growth of SK-MEL-28 cells.

2011-06-24 | GSE23930 | GEO

Genome-wide transcriptome profiling of SK-Mel-28, UACC-62 and HCT-116 cells stably expressing scrambled shRNA and RAB7 shRNA

Project description:Purpose: Assess the transcriptional changes induced upon RAB7 knock-down in melanoma (SK-Mel-28 and UACC-62) and in colon cancer (HCT-116) cell lines. Methods: mRNA profiles of tumor cell lines (SK-Mel-28, UACC-62, HCT-116) stably expressing scrambled shRNA or RAB7 shRNA (harvested at day 3 after lentiviral infection) were generated by deep sequencing, using three biological replicates per condition. The sequence reads that passed quality filters were analyzed with TopHat and Cufflinks. Validation of induced / silenced genes was performed by western blot. Results show a differential impact of RAB7 expression in the transcriptomic profile of melanoma vs non-melanoma cell lines, and support a lineage-specific role of this small GTPase in melanoma. Examination of the mRNA profiles RAB7-depleted vs wild type cells, performed in parallel in 3 different tumor cell lines (Melanomas: SK-Mel-28 and UACC-62, Non-melanoma: HCT-116) harvested at day 3 after lentiviral infection.

2014-04-20 | E-GEOD-42735 | biostudies-arrayexpress

Lentiviral shRNA library screen to identify growth-related genes in malignant melanoma

Project description:Little is known about genes that promote melanoma cell growth and proliferation. siRNAs may be used to address the role of individual genesin these processes. RNAi library screens were used in the past to gain a comprehensive overview of all genes involved in cell growth, proliferation, migration and other cellular processes. A large-scale loss-of-function screen for eight different melanoma cell lines was performed using a pooled lentiviral shRNA library (GeneNet Human 50K lentiviral shRNA Library,cat#SI206B-1, System Biosciences) to identify genes relevant for melanoma cell growth and proliferation. shRNAs that lead to cell death or reduced growth of transduced melanoma cells are negatively selected and thereby underrepresented in the final cellular shRNA pool and vice versa. The shRNAs of the shRNA library (3-5 per gene) have complementary sequences to probes on the custom Affymetrix microarray HG-U133Plus2 and were analysed using this array. Well-known melanoma cell lines SK-Mel-103, A375, SK-Mel-147, SK-Mel-19, SK-Mel-28, SK-Mel-29, SK-Mel-5, WM3523cln6 were transduced with the lentiviral shRNA library and grown for 10 days under puromycin selection (day 10), control cells of respective cell lines were transduced and frozen immediately after transduction and genomic integration of shRNAs (day 0). Totel DNA was extracted and genomically integrated shRNAs were hybridized to Affymetrix microarrays (HG-U133Plus2.0 array).

2014-01-24 | E-GEOD-46675 | biostudies-arrayexpress

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