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The RALA pathway can maintain the proliferation of KRAS- and BRAF-mutated cancer cells

ABSTRACT: By silencing of RALA, a downstream member of the RAS signal transduction pathway, we aimed to determine whether genes downstream of a mutated KRAS (codon 12 or 13) or a mutated BRAF can have significant functions in colorectal cancer carcinogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE39857 | GEO | 2015/06/20

SECONDARY ACCESSION(S): PRJNA171925

REPOSITORIES: GEO

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The RALA pathway can maintain the proliferation of KRAS- and BRAF-mutated cancer cells

Project description:By silencing of RALA, a downstream member of the RAS signal transduction pathway, we aimed to determine whether genes downstream of a mutated KRAS (codon 12 or 13) or a mutated BRAF can have significant functions in colorectal cancer carcinogenesis. RALA was silenced in three colorectal cancer cell lines (SW480, HCT116 and HT29). Effects were normalized to mock-transfected cells and the effects of scramble siRNA were excluded. SW480, HCT116 and HT29 cell lines were treated with the PI3K inhibitor LY294002 or DMSO.

2015-06-20 | E-GEOD-39857 | biostudies-arrayexpress

BRAF siRNA NHGRI_Liang_BRAF

Project description:BRAF, one of three RAF serine/threonine kinases (ARAF, BRAF and CRAF), plays a major role in the RAS-RAF-MEK-ERK mitogen-activated protein kinase (MAPK) signaling pathway, which mediates cellular responses to growth signals. Recently a high frequency (~60%-70%) of activating BRAF mutations (predominantly V600E) has been reported in malignant melanoma. In order to identify the downstream effects of BRAF signaling on melanoma cell growth and gene expression, cDNA microarray analysis was carried out following BRAF siRNA or MEK1/2 inhibitor (U0126) treatment. Keywords: time series, siRNA time series, siRNA, drug treatment

2013-07-07 | E-GEOD-5481 | biostudies-arrayexpress

BRAF siRNA NHGRI_Liang_BRAF

2013-07-07 | GSE5481 | GEO

BRAF activation by metabolic stress promotes glycolysis and survival, sensitizing NRASQ61 mutated melanomas to targeted therapy.

Project description:NRAS-mutated melanoma lacks an approved first-line treatment. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknow how the NRAS oncogene contributes to this cancer hallmark. Here, we show that NRASQ61-mutated melanomas harbor specific metabolic alterations that render cells sensitive to sorafenib upon metabolic stress. Mechanistically, these cells seem to depend on glucose metabolism, as glucose deprivation promotes the switch of the RAF isoform used from CRAF to BRAF. This process contributes to cell survival and sustains glucose metabolism through the phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/6- phosphofructo-2-kinase/fructose-2,6-bisphosph 3 (PFKFB2/PFKFB3) heterodimers by BRAF. In turn, this phosphorylation favors the allosteric activation of phosphofructokinase-1 (PFK1), generating a feedback loop linking glycolysis and the RAS signaling pathway. In vivo treatment of NRASQ61 mutant melanomas, including patient-derived xenografts, with the combination of 2-deoxy-D-glucose (2-DG) and sorafenib effectively inhibits tumor growth. Thus, we provide evidence of the contributions of NRAS oncogenes to metabolic rewiring and proof of principle for the treatment of NRAS-mutated melanoma with combinations of metabolic stress (glycolysis inhibitors) and already approved drugs such as sorafenib.

2023-01-09 | PXD028297 | Pride

Targeted treatment for KRAS/BRAF-mutated and BCL2L1-amplified CRCs

Project description:A novel combination treatment targeting BCL2L1 and MCL1 for KRAS/BRAF-mutated and BCL2L1-amplified colorectal cancers

| PRJEB20153 | ENA

BRAF-induced tumorigenesis is IKKalpha dependent but NF?B independent

Project description:Tumor cells carrying KRAS mutations activate the NF-?B pathway by different mechanisms, which contribute to the acquisition of essential cancer properties. The BRAF kinase, a downstream mediator of KRAS, is also mutated in a subset of colorectal cancers (CRC), which predicts bad prognosis and therapy resistance. However, nothing is known on whether NF-?B participates of BRAF-mediated tumorigenesis. We here found that in CRC cells, mutant BRAF does not trigger canonical or alternative NF-?B signaling but induces p45-IKK? activation. Moreover, IKK? activity is required for BRAF-induced transformation and to support BRAF-dependent transcription in CRC cells. Activation of p45-IKK? downstream of BRAF requires the TAK1 kinase, and is associated to the endosomal compartment. Inhibition of endosomal V-ATPase abolished p45-IKK? phosphorylation, and induced apoptosis of BRAF mutated CRC cells. Pharmacologic inhibition of endosome acidification reduced the in vivo growth of tumors carrying mutant BRAF, and abrogated the metastatic capacity of a primary human CRC tumor with acquired resistance to standard chemotherapy in an orthotopic xenograft model. 18 samples were analyzed: HT29 controls (n=3); HT28 BRAF inhibited (n=3), WiDr controls (n=3); WiDr BRAF inhibited (n=3); WiDr transduced with control shRNA (n=3) and WiDr transduced with shRNA against IKKalpha (n=3)

2015-05-08 | E-GEOD-57979 | biostudies-arrayexpress

BRAF-induced tumorigenesis is IKKalpha dependent but NFκB independent

Project description:Tumor cells carrying KRAS mutations activate the NF-κB pathway by different mechanisms, which contribute to the acquisition of essential cancer properties. The BRAF kinase, a downstream mediator of KRAS, is also mutated in a subset of colorectal cancers (CRC), which predicts bad prognosis and therapy resistance. However, nothing is known on whether NF-κB participates of BRAF-mediated tumorigenesis. We here found that in CRC cells, mutant BRAF does not trigger canonical or alternative NF-κB signaling but induces p45-IKKα activation. Moreover, IKKα activity is required for BRAF-induced transformation and to support BRAF-dependent transcription in CRC cells. Activation of p45-IKKα downstream of BRAF requires the TAK1 kinase, and is associated to the endosomal compartment. Inhibition of endosomal V-ATPase abolished p45-IKKα phosphorylation, and induced apoptosis of BRAF mutated CRC cells. Pharmacologic inhibition of endosome acidification reduced the in vivo growth of tumors carrying mutant BRAF, and abrogated the metastatic capacity of a primary human CRC tumor with acquired resistance to standard chemotherapy in an orthotopic xenograft model.

2015-05-08 | GSE57979 | GEO

Deciphering KRAS and NRAS mutated clones dynamics in MLL-AF4 pediatric leukemia by ultra deep sequencing analysis

Project description:We studied the KRAS and NRAS mutational status in pediatric MLL-AF4+ leukemia patients by means of ultra deep amplicon sequencing. The gene expression profiles of RAS wild type and RAS mutated patients were investigated by gene expression analysis. We showed that mutated patients were characterized by a RAS related expression signature.

2016-10-04 | GSE77416 | GEO

microRNA expression profile between KRAS/BRAF wild and BRAF mutant colorectal cancer

Project description:The genome-wide miRNA expression analysis was performed in clinical samples, comprising 15 BRAF-mutant and 15 non-KRAS/BRAF-mutant colorectal cancers by using a SurePrint G3 Human miRNA microarray. clinical samples, comprising 15 BRAF-mutant and 15 non-KRAS/BRAF-mutant colorectal cancers by using a SurePrint G3 Human miRNA microarray.

2016-04-01 | E-GEOD-66548 | biostudies-arrayexpress

Transcriptional profiles of NRAS- and BRAF-mutant melanoma cell lines under normal conditions and in response to glucose starvation

Project description:NRAS and BRAF are the most commonly found genetic alterations in melanoma. It has been demonstrated that NRAS and BRAF oncogenic alterations, even affecting the same signaling pathway, represent two different clinical and biochemical entities, showing different signaling patterns and biological responses. Metabolic reprogramming is considered a novel target to control cancer; however, it is mostly unknown how the NRAS oncogene contributes to this cancer hallmark. We have showed that NRAS-mutated melanomas harbor specific metabolic alterations that render cells sensitive to RAS pathway inhibition upon metabolic stress. Gene expression analysis has confirmed different transcriptional profiles of NRAS- and BRAF- mutant cells both, under basal conditions and in response to glucose starvation. Moreover, analysis of glucose metabolism-related genes expression regulation revealed PFKFB2 as an important player linking glycolysis and RAS pathway activation.

2022-08-31 | E-MTAB-10921 | biostudies-arrayexpress

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