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3' RNAseq of EGFR mutant lung cancer cell line overexpressing BRAF V600E treated with inhibitors

ABSTRACT: 3' RNAseq of EGFR mutant lung cancer cell line overexpressing BRAF V600E treated with inhibitors

PROVIDER: PRJEB47888 | ENA |

REPOSITORIES: ENA

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3' RNAseq of EGFR mutant lung cancer cell line overexpressing BRAF V600E treated with inhibitors

Project description:In the human EGFR mutant adenocarcinoma cell line PC9 pBabe empty vector (EV) or BRAF V600E were overexpressed. RNA was extracted from EV, BRAF V600E overexpressing or osimertinib-resistant BRAF V600E expressing cells after 48h treatment with osimertinib, trametinib, a combination of both or vehicle controls. RNA was subjected to 3' UTR RNA sequencing.

2021-10-20 | E-MTAB-11004 | biostudies-arrayexpress

Transcriptional Response to transgenic BRAF(V600E) in the intestinal epithelium

Project description:BRAF(V600E) is a frequent mutation in colon cancer. We have analysed transcriptional effects of BRAF(V600E) in the intestinal epithelium of transgenic mice that harbour an inducible BRAF(V600E) transgene. Mice used in this experiment were compound transgenic for a stem-cell specific Lgr5-EGFP Reporter and either an inducible TdTomato-2A-BRAF(V600E) transgene or an inducibe TdTomato-luciferase transgene. Transgenes were induced by doxycycline (4mg/ml) treatment provided in a 1% sucrose solution in the drinking water of transgenic mice for 24h. Intestinal crypts were isolated by filtering (70um) following a PBS/EDTA incubation step. Single cell suspensions were made by digestion of crypts in 500ug/ml trypsine and 0.8u/ml DNAseI for approx. 20min at RT. Cell populations for profiling were isolated by FACS, using an Aria SOPR (BD), equipped with a 70um nozzle.

2013-12-31 | E-GEOD-50678 | biostudies-arrayexpress

Genomics characterization of BRAF-V600E colorectal cancer patients treated with anti-BRAF/EGFR

Project description:Anti-BRAF/EGFR combinatorial therapy was recently approved by the FDA and EMA for the treatment of metastatic BRAF-V600E colorectal cancer (CRCBRAF-V600E), however the underlying genetic determinants of its anti-tumoral efficacy remain unknown. Using whole-exome sequencing data in an internal cohort of CRCBRAF-V600E treated with anti-BRAF/EGFR Ã‚Â± combinatorial therapies, we discovered that patients with MSS-RNF43mutated tumors achieved a higher ORR in comparison with MSI-RNF43mutated and MSS-RNF43wild-type. Multivariate analysis of an external validation cohort showed improved PFS and OS of MSS-RNF43mutated in comparison with MSS-RNF43wild-type. In vitro assessment of RNF43 mutations identified in MSS tumors showed a loss-of-function effect. Overall, our findings support a crucial role of the RNF43-dependent modulation of the WNT pathway in the antitumor activity of anti-BRAF/EGFR Ã‚Â± combinatorial therapies and may guide patient stratification strategies for future clinical studies.

| EGAS00001006247 | EGA

Oncogenic KRAS(G12V) and BRAF(V600E) in intestinal organoids

Project description:Goals of the study was to compare transcripional and phenotypic response of mouse intestinal organoid cultures to the KRAS(G12V) or BRAF(V600E)oncogenes.

2018-06-02 | GSE115234 | GEO

Human BRAF-V600E melanoma cell lines drug sensitive vs drug resistant

Project description:aCGH of human melanoma cell lines comparing parental (drug sensitve) vs isogenic drug resistant-derived subline Two condition experiment: two BRAF-V600E mutant cell lines (drug sensitive - parental baseline) vs two derived sublines after chronic exposure to the MEK inhibitor trametinib (drug resistant) are compared

2014-04-21 | E-GEOD-49430 | biostudies-arrayexpress

BRAF-V600E utilizes post-transcriptional mechanisms to amplify LPS-induced TNF production in dendritic cells of Langerhans Cell Histiocytosis

Project description:Langerhans Cell Histiocytosis (LCH) is an inflammatory disease characterized by abnormal dendritic cells (DCs) with hyperactive ERK signaling, called “LCH cells”. Since DCs rely on ERK signaling to produce inflammatory signaling molecules in response to pathogenic cues, we hypothesized that hyperactive ERK will enhance DC inflammatory responses. We utilized the BRAF-V600E fl/+: CD11c-Cre mouse model of LCH which hyperactivates MAPK/ERK signaling in DCs. We cultured bone-marrow derived dendritic cells (BMDCs) from LCH and control mice (BRAF-V600E fl/+: Cre0) and stimulated them with LPS with or without a specific BRAF-V600E inhibitor. Polysome Profiling revealed a large and irreversible increase in levels of polysome bound RNA in the LCH-BMDCs compared to WT. We defined the LCH translatome by analyzing total and polysome-bound RNA from BMDCs using the Anota2seq program, which revealed a BRAF-V600E-mediated selective increase in LPS-induced inflammatory proteins.

2022-05-01 | GSE193610 | GEO

Novel prognostic implications of complement activation in the tumor microenvironment for de novo metastatic BRAF V600E mutant colorectal cancer

Project description:Prognosis of metastatic BRAF V600E mutant colorectal cancer (CRC) is poor, and the prognostic implications of immune contextures in the tumor microenvironment (TME) for CRC remain elusive. Complement activation in the TME was significantly associated with poor OS and was correlated with TAM M2 in patients with de novo metastatic BRAF V600E mutant CRC.

2022-11-08 | GSE211576 | GEO

Braf inhibitors reverse the unique molecular signature and phenotype of hairy cell leukemia, and exert anti-leukemic activity

Project description:Hairy cell leukemia (HCL) shows unique clinico-pathological and biological features. HCL responds well to purine analogues but relapses are frequent and novel therapies are required. BRAF-V600E is the key driver mutation in HCL and distinguishes it from other B-cell lymphomas, including HCL-like leukemias/lymphomas (HCL-variant and splenic marginal zone lymphoma). The kinase-activating BRAF-V600E mutation also represents an ideal therapeutic target in HCL. Here, we investigated the biological and therapeutic importance of the activated BRAF-MEK-ERK pathway in HCL by exposing in vitro primary leukemic cells purified from 26 patients to clinically available BRAF (Vemurafenib; Dabrafenib) or MEK (Trametinib) inhibitors. Results were validated in vivo in samples from Vemurafenib-treated HCL patients within a phase-2 clinical trial. BRAF and MEK inhibitors caused, specifically in HCL (but not HCL-like) cells, marked MEK/ERK dephosphorylation, silencing of the BRAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression signature, downregulation of the HCL markers CD25, TRAP and cyclin-D1, smoothening of leukemic cells' hairy surface, and, eventually, apoptosis. Apoptosis was partially blunted by co-culture with bone marrow stromal cells antagonizing MEK-ERK dephosphorylation. This protective effect could be counteracted by combined BRAF and MEK inhibition. Our results strongly support and inform the clinical use of BRAF and MEK inhibitors in HCL. Analysis of differential gene expression in primary leukemic cells purified from peripheral blood of 6 HCL patients (from A to F), treated with Vemurafenib 1000 nM, in comparison with vehicle-treated (DMSO) HCL cells, for 48 hours or/and 72 hours. 24 gene expression profiles were analysed.

2014-12-12 | E-GEOD-63790 | biostudies-arrayexpress

A system-wide approach to monitor responses to synergistic BRAF and EGFR inhibition in colorectal cancer cells

Project description:Molecular heterogeneity of tumors, epigenetic changes and a diverse range of molecular mechanisms are main contributors to drug resistance, which represents one of the great challenges in cancer treatment. A deeper understanding of the molecular biology of cancer has resulted in better targeted therapies, where one or multiple drugs are adopted in novel therapies to tackle resistance. This beneficial effect of using combination treatments has to some extent also been observed in colorectal cancer (CRC) patients harboring the BRAF(V600E) mutation, whereby dual inhibition of BRAF(V600E) and EGFR increases antitumor activity. Notwithstanding this success, it is not clear whether this combination treatment is the only or most effective treatment to block resistance. Here, we investigate molecular responses upon single and multi-target treatments, over time, using BRAF(V600E) mutant CRC cells as a well-define model system. Through integration of transcriptomic, proteomic and phosphoproteomics data we obtain a comprehensive overview, revealing both well-known and novel responses. We primarily observe widespread upregulation of tyrosine kinases (RTKs) and and metabolic pathways. This points to by which the treated cells switch energy sources as a defensive response entering a quiescent like state, while activating signalling to re-activate the MAPK pathway.

2018-07-16 | PXD007740 | Pride

Gene expression changes induced by transgenic expression of CCDC6-RET or BRAF(V600E) oncogenes in zebrafish thyroid tumors [Zebrafish RET vs BRAF adult tumors]

Project description:We used RNAseq to examine gene expression changes in thyroid tumors arising in transgenic zebrafish engineered to expression human CCDC6-RET or BRAF(V600E) oncogenes

2022-03-23 | GSE199023 | GEO

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