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Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)

ABSTRACT: Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)

PROVIDER: PRJNA562870 | ENA |

REPOSITORIES: ENA

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Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)

Project description:BRAF V600 mutation influences cellular signaling pathways for melanoma development. Here, we show that mutated BRAF plays an essential role in the adaptive stress response following activation of general control non-derepressible 2 (GCN2) kinase. In parallel with GCN2, BRAF ensures ATF4 induction by utilizing mTOR and eIF4B as downstream regulators during nutrient stress and BRAF-targeted, therapeutic stress. Upon pharmacological BRAF inhibition, this signaling pathway exhibits temporal resistance, compared with the MEK-ERK pathway, thereby enabling transient induction of ATF4 under GCN2 activation. Notably, the prevention of GCN2 activation, using a chemical inhibitor that we identified, produces synergistic cell killing with BRAF inhibition. Thus, oncogenic BRAF can collaborate with the GCN2–ATF4 pathway, promoting stress adaptation for cell survival.

2020-04-06 | GSE136614 | GEO

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)

2020-04-06 | GSE136613 | GEO

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy

Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy

| PRJNA562868 | ENA

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)

Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)

| PRJNA562871 | ENA

Disrupting ATF4 Expression Mechanisms Provides an Effective Strategy for BRAF-Targeted Melanoma Therapy.

Project description:BRAF V600 mutation influences cellular signaling pathways for melanoma development. However, the role of oncogenic BRAF in adaptive stress response pathways is not fully understood. Here, we show that oncogenic BRAF plays an essential role in the induction of ATF4 following the activation of general control non-derepressible 2 (GCN2) kinase during nutrient stress and BRAF-targeted, therapeutic stress. Under GCN2 activation, BRAF ensures ATF4 induction by utilizing mTOR and eIF4B as downstream regulators. In contrast to the MEK-ERK pathway, this signaling pathway remains temporarily active even during treatment with BRAF inhibitors, thereby enabling the transient induction of ATF4. We also identify a chemical compound that prevents BRAF inhibitor-induced activation of the GCN2-ATF4 pathway and produces synergistic cell killing with BRAF inhibitors. Our findings establish a collaborative relationship between oncogenic BRAF and the GCN2-ATF4 signaling pathway, which may provide a novel therapeutic approach to target the adaptive stress response.

| S-EPMC7155235 | biostudies-literature

Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-05 | GSE136615 | GEO

HDX-MS data on bRaf, bRaf/Cdc37 and bRaf/Cdc37/Hsp90 protein complexes

Project description:HDX-MS data on bRaf, bRaf/Cdc37 and bRaf/Cdc37/Hsp90 protein complexes

2022-01-04 | MSV000088635 | MassIVE

ATF4 coordinates amino acid and nucleotide synthesis with selective protein translation to ensure proper DNA replication timing in leukemia cells

Project description:Proper timing of DNA replication relies on sufficient nucleotide pools and replication machinery. The upstream regulatory programs that support the biomass production that is required for DNA replication, particularly in the accelerated growth setting of cancer, remain incompletely defined. Here we show that the transcription factor ATF4 coordinates amino acid and nucleotide metabolism with selective protein synthesis to ensure proper DNA replication initiation and timing in acute leukemia. Specifically, ATF4 promotes the expression of enzymes that biosynthesize amino acids required for nucleotide production and drive the transcription of tRNA charging enzymes that sustain translation of a subset of proteins involved in replication origin firing. Consequently, ATF4 inhibition limits nucleotide biosynthesis and replication machinery, thereby disrupting DNA replication timing and leading to leukemia cell differentiation and death.Our findings indicate that ATF4 coordinates metabolic and translational programs to maintain DNA replication fidelity in leukemia cells.

2026-02-20 | PXD074631 | Pride

CDK4/6 and SHP2 mediate BRAF/MEK inhibitor resistance in Class 2 and 3 BRAF mutant cancers

Project description:Class 2 and 3 non-V600E BRAF mutations are oncogenic drivers in many cancer types. Currently, there are no established targeted therapies with proven efficacy for cancers with non-V600E BRAF mutations. We developed the investigator-initiated, Phase II BEAVER clinical trial (NCT03839342) to evaluate the efficacy of BRAF and MEK inhibitors in patients with non-V600E BRAF mutations. The best objective response rate was 14% (3/21). By analyzing genomic data from patient tumors, circulating tumor DNA (ctDNA), patient-derived xenograft (PDX) models generated from enrolled patients, and Class 2 & 3 BRAF mutant cell lines, we discovered MAPK-dependent and independent mechanisms of resistance to BRAF/MEK inhibition. These mechanisms included the acquisition of new mutations in NRAS, MAP2K1, RAF1, and RB in ctDNA at the time of disease progression. CDK4/6 and SHP2 were identified as mediators of intrinsic resistance to BRAF/MEK inhibition in Class 2 & 3 BRAF mutant tumors. Therapeutic strategies combining CDK4/6 or SHP2 inhibitors with BRAF/MEK inhibitors were more effective than BRAF/MEK inhibitors alone in these cancers. https://doi.org/10.1038/s41467-025-68076-7

2025-11-11 | GSE308451 | GEO

Effect of muscle-specific ATF4 gene knockout (ATF4 mKO) on skeletal muscle mRNA levels in aged mice.

Project description:For additional details see Ebert et al, Identification and Small Molecule Inhibition of an ATF4-dependent Pathway to Age-related Skeletal Muscle Weakness and Atrophy. Quadriceps femoris muscles were harvested from 22-month-old muscle-specfic ATF4 knockout (ATF4 mKO) mice and littermate controls. mRNA levels in ATF4 mKO muscles were normalized to levels in littermate control muscles.

2015-09-03 | E-GEOD-72658 | biostudies-arrayexpress

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