Similar Datasets
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
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
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 | GSE136613 | GEO
Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy
| PRJNA562868 | ENA
Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Knockdown Series)
| PRJNA562870 | ENA
Project description:Disrupting ATF4 expression mechanisms provides an effective strategy for BRAF-targeted melanoma therapy (Drug Treatmant Series)
| PRJNA562871 | ENA
Project description:Patients with metastatic melanoma have historically had dismal outcomes. The last several years has seen the emergence of effective immune and targeted therapies for metastatic melanoma. Targeted therapies have primarily impacted the 40-50% of patients with BRAF(V600) mutated melanoma. The remainder of patients with advanced melanoma harbor a wide spectrum of mutations other than BRAF(V600) that are associated with unique pathophysiological, prognostic, and therapeutic implications. The treatment of this subset of patients is a challenging problem. In recent years, preclinical and early clinical studies have suggested that inhibitors of mitogen activated protein kinase (MAPK) pathway and parallel signaling networks may have activity in treatment of BRAF(V600) wild-type (WT) melanoma. In this review, we will discuss available and developing therapies for BRAF WT patients with metastatic melanoma, particularly focusing on molecular targeted options for various genetically defined melanoma subsets.
| S-EPMC10203820 | biostudies-literature
Project description:Mutant serine/threonine protein kinase B-Raf (BRAF) protein is expressed in over half of all melanoma tumors. Although BRAF inhibitors (BRAFi) elicit rapid anti-tumor responses in the majority of patients with mutant BRAF melanoma, the tumors inevitably relapse after a short time. We hypothesized that polyamines are essential for tumor survival in mutant BRAF melanomas. These tumors rely on both polyamine biosynthesis and an upregulated polyamine transport system (PTS) to maintain their high intracellular polyamine levels. We evaluated the effect of a novel arylpolyamine (AP) compound that is cytotoxic upon cellular entry via the increased PTS activity of melanoma cells with different BRAF mutational status. Mutant BRAF melanoma cells demonstrated greater PTS activity and increased sensitivity to AP compared to wild type BRAF (BRAFWT) melanoma cells. Treatment with an inhibitor of polyamine biosynthesis, ?-difluoromethylornithine (DFMO), further upregulated PTS activity in mutant BRAF cells and increased their sensitivity to AP. Furthermore, viability assays of 3D spheroid cultures of mutant BRAF melanoma cells demonstrated greater resistance to the BRAFi, PLX4720, compared to 2D monolayer cultures. However, co-treatment with AP restored the sensitivity of melanoma spheroids to PLX4720. These data indicate that mutant BRAF melanoma cells are more dependent on the PTS compared to BRAFWT melanoma cells, resulting in greater sensitivity to the PTS-targeted cytotoxic AP compound.
| S-EPMC5872160 | biostudies-literature
Project description:Purpose of reviewThe treatment strategy for BRAF-mutated melanoma remains unsatisfactory, although the advent of immune checkpoint inhibition has improved the prognosis of advanced melanoma. This article reports current evidence on the efficacy and safety of sequential immunotherapy with targeted therapy in patients with BRAF-mutated melanoma. It discusses criteria for the use of available options in clinical practice.Recent findingsTargeted therapy provides rapid disease control in a relatively high proportion of patients, although the development of secondary resistance limits the duration of responses; in contrast, immunotherapy may induce slow but more durable responses in a subset of patients. Therefore, the identification of a combination strategy for the use of these therapies seems a promising perspective. Currently, inconsistent data have been obtained, but most studies indicate that the administration of BRAFi/MEKi prior to immune checkpoint inhibitors appears to reduce the efficacy of immunotherapy. On the contrary, several clinical and real-life studies suggest that frontline immunotherapy with subsequent targeted therapy may be associated with better tumor control than immunotherapy alone. Larger clinical studies are ongoing to confirm the efficacy and safety of this sequencing strategy for treating BRAF-mutated melanoma with immunotherapy followed by targeted therapy.
| S-EPMC10164000 | biostudies-literature
Project description:Introduction: Immune checkpoint inhibitor therapy and BRAF-targeted therapy have been developed for the treatment of metastatic melanoma. The optimal use of these agents, either in sequence or combination, for the 40-50% of melanoma patients whose tumors harbor a BRAFV600 mutation is unknown, but data from a number of clinical trials, including one randomized Phase II study, are emerging.Areas covered: This review describes the preclinical and clinical rationale for combined BRAF-targeted therapy with immunotherapy, including the known effects of BRAF-targeted therapy on the immune microenvironment, and the clinical trial data from a number of studies.Expert opinion: BRAF-targeted therapy is associated with high response rates in patients with metastatic melanoma but also leads to changes in the tumor microenvironment that may sensitize these tumors to immunotherapy. The early trials of BRAF-targeted therapy with immunotherapy, in particular with anti-PD-1/PD-L1 agents, are encouraging and suggest that some patients may benefit from this treatment approach. However, incorporating these combinations into routine clinical practice requires the read-out from two randomized clinical trials expected in the coming 1-2 years.
| S-EPMC7150269 | biostudies-literature