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Multi range ERK responses shape the proliferative trajectory of single cells following oncogenic induction

ABSTRACT: Aberrant oncogene activation can promote cellular transformation and tumorigenesis, enabling cancer cells to grow and proliferate uncontrollably. For instance, activating Ras or Raf mutations bypass the need of growth factor stimulation, resulting in constitutive mitogenic signaling through the Ras or Raf to MAPK pathway. Surprisingly, in normal cells, the same oncogenic mutations typically cause cells to enter into a stable state of cell cycle arrest, a phenomenon known as oncogene-induced senescence. We hypothesized that players that mediate ERK activity-dependent cell fate decisions must themselves undergo some expression/activity changes in response to varying levels of ERK activity. To systematically identify gene expression changes associated with different levels of ERK activity, we performed deep RNA sequencing of RPE cells simultaneously treated, for varying lengths of time, with DOX (to induce BRAFV600E) and different concentrations of ERK inhibitors. The ERK inhibitor concentrations were chosen to include most dynamic ranges of proliferation response based on previous titration experiments. The time points include 0 (untreated control), 1, 2, 4, 8, 16 and 24h post DOX and drug treatment. These time points were selected based on the observation that RPE cells already showed a bell-shaped correlation between ERK activity and proliferation as early as 24h after BRaf induction. Moreover, earlier time points allow enrichment of genes that are more directly responsive to ERK activity changes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE180210 | GEO | 2021/07/16

REPOSITORIES: GEO

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Pan-Raf co-operates with PI3K-dependent signaling and critically contributes to myeloma cell survival independently of mutated RAS

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Characterization of RAS/RAF/ERK signal cascade as a novel regulating factor in alpha-amanitin-induced liver injury

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

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Project description:The oncogenic proteins expressed in human cancer cells are exceedingly difficult targets for drug discovery due to intrinsic properties of the Ras GTPase switch. As a result, recent efforts have largely focused on inhibiting Ras-regulated kinase effector cascades, particularly the Raf/MEK/ERK and PI3 kinase/Akt/mTOR pathways. We constructed murine stem cell leukemia virus (MSCV) vectors encoding oncogenic K-RasD12 with additional “second site” amino acid substitutions that that impair PI3 kinase/Akt or Raf/MEK/ERK activation and performed bone marrow transduction/transplantation experiments in mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins induced aggressive clonal T lineage acute lymphoblastic leukemia (T-ALL). These leukemias exhibited a high frequency of somatic Notch1 mutations, which is also true of human T-ALL. Multiple independent T-ALLs restored full oncogenic Ras activity by acquiring “third site” mutations within the viral KrasD12 transgenes. Other leukemias with undetectable PTEN and elevated phosphoryated Akt levels showed a similar gene expression profile to human early T progenitor (ETP) T-ALL. Expressing oncoproteins that are defective for specific functions is a general strategy for assessing requirements for tumor maintenance and uncovering potential mechanisms of drug resistance in vivo. In addition, our observation that defective Kras oncogenes regain potent cancer initiating activity strongly supports simultaneously targeting distinct components of Ras signaling networks in the substantial fraction of cancers with RAS mutations. WT Balb/c mice were lethally irradiated and transplanted with WT Balb/c bone marrow cells transduced with MSCV-IRES-Kras mutant-GFP vectors. Mice developed T-cell lymphoproliferative disease.

2011-09-30 | E-GEOD-28687 | biostudies-arrayexpress

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2023-03-08 | GSE224215 | GEO

MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors, despite transcriptional feedback onto ERK.

Project description:Neurofibromatosis Type 1 (NF1) patients develop benign neurofibromas and malignant peripheral nerve sheath tumors (MPNST). These incurable peripheral nerve tumors result from loss of NF1 tumor suppressor gene function, causing hyperactive Ras signaling. Activated Ras controls numerous downstream effectors, but specific pathways mediating effects of hyperactive Ras in NF1 tumors are unknown. Cross-species transcriptome analyses of mouse and human neurofibromas and MPNSTs identified global negative feedback of genes that regulate Ras-Raf- MEK- extracellular signal-regulated protein kinase (ERK) signaling in both species. Nonetheless, activation of ERK was sustained in mouse and human neurofibromas and MPNST. PD0325901, a highly selective pharmacological inhibitor of MEK, was used to test whether sustained Ras-Raf-MEK-ERK signaling contributes to neurofibroma growth in the Nf1fl/fl;Dhh-cre mouse model or in NF1 patient MPNST cell xenografts. PD0325901 treatment reduced aberrantly proliferating cells in neurofibroma and MPNST, prolonged survival of mice implanted with human MPNST cells, and shrank neurofibromas in >80% of mice tested. PD0325901 also caused effects on tumor vasculature. Our data demonstrate that deregulated Ras/ERK signaling is critical for the growth of NF1 peripheral nerve tumors and provide strong rationale for testing MEK inhibitors in NF1 clinical trials.

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Functional characterization of a PROTAC directed against BRAFV600E

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2020-05-25 | GSE148500 | GEO

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