BRAF (gène) | EPFL Graph Search

BRAF est un gène humain situé sur le chromosome 7 et responsable de la production de la protéine B-Raf. Le gène est aussi appelé B-Raf proto-oncogène, tandis que la protéine est mieux connu sous le nom de protéine B-Raf sérine/thréonine kinase B-Raf. La protéine B-Raf est impliquée dans l'envoi des signaux qui déterminent la croissance des cellules au sein de celles-ci. Elle est présente sous une forme mutée dans certains cancers touchant l'humain. Certaines autres mutations de BRAF héréditaires provoquent des malformations congénitales. Des médicaments pour traiter les cancers causés par les mutations du gène BRAF ont été développés. La présence d'une mutation de BRAF dans une cellule cancéreuse rend en effet cette dernière totalement dépendante de BRAF pour sa survie, par le mécanisme d'addiction oncogénique. Deux de ces traitements, le vemurafenib et le dabrafenib ont été approuvés par la FDA pour le traitement du mélanome au stade avancé. Sources Catégorie:Chromo

Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition

Christoph Schwärzler

Tumor plasticity and the heterogeneous response of melanoma cells to targeted therapies are major limits for the long-term efficacy of this line of therapy. Targeting tumor plasticity is theoretically possible through the modulation of the expression of RNA-binding proteins which can affect many different compensatory mechanisms of the adaptive response of malignant cells to targeted therapies. Human antigen R (HuR) is a modulator of gene expression and a transacting factor in the mRNA-processing machinery used in the cell stress response, and is a potential target for reducing tumor plasticity. In this experiment, we exploit the inherent heterogeneous response of the A375 melanoma line to suboptimal BRAF inhibition as a model of immediate adaptive response. We first observe that HuR overexpression can prevent the heterogeneous response and thus the immediate paradoxical proliferation induced by low-doses vemurafenib treatment. We then use single-cell mass cytometry to characterize subpopulations, including those that paradoxically proliferate, based on their proliferation rate and the expression patterns of markers involved in the reversible adaptive resistance to BRAF inhibition and/or recognized as HuR targets involved in cell cycle regulation. Under suboptimal BRAF inhibition, HuR overexpression affects these subpopulations and their expression pattern with contrasting responses depending on their proliferation rate: faster-proliferating vemurafenib-sensitive or -resistant subpopulations showed higher death tendency and reduced size, and slower-proliferating subpopulations showed an attenuated resistant expression response and their paradoxical proliferation was inhibited. These observations pave the way to new therapeutic strategies for preventing the heterogeneous response of tumors to targeted therapies.

Wiley2017

Identification of New Vulnerabilities in Conjunctival Melanoma Using Image-Based High Content Drug Screening

Fabien Kuttler, Olivier Michielin, Mathieu Quinodoz, Gerardo Turcatti

Recent evidence suggests that numerous similarities exist between the genomic landscapes of both conjunctival and cutaneous melanoma. Since alterations of several components of the MAP kinases, PI3K/mTOR, and cell cycle pathways have been reported in conjunctival melanoma, we decided to assess the sensitivity of conjunctival melanoma to targeted inhibition mostly of kinase inhibitors. A high content drug screening assay based on automated fluorescence microscopy was performed in three conjunctival melanoma cell lines with different genomic backgrounds with 489 kinase inhibitors and 53 other inhibitors. IC50 and apoptosis induction were respectively assessed for 53 and 48 compounds. The genomic background influenced the response to MAK and PI3K/mTOR inhibition, more specifically cell lines with BRAF V600E mutations were more sensitive to BRAF/MEK inhibition, while CRMM2 bearing the NRASQ61L mutation was more sensitive to PI3k/mTOR inhibition. All cell lines demonstrated sensitivity to cell cycle inhibition, being more pronounced in CRMM2, especially with polo-like inhibitors. Our data also revealed new vulnerabilities to Hsp90 and Src inhibition. This study demonstrates that the genomic background partially influences the response to targeted therapy and uncovers a large panel of potential vulnerabilities in conjunctival melanoma that may expand available options for the management of this tumor.

2022

Improving Efficacy and Safety of Agonistic Anti-CD40 Antibody Through Extracellular Matrix Affinity

Martina Damo, Kazuto Fukunaga, Jeffrey Alan Hubbell, Jun Ishihara, Lambert Charles François Potin, Melody Swartz

CD40 is an immune costimulatory receptor expressed by antigen-presenting cells. Agonistic anti-CD40 antibodies have demonstrated considerable antitumor effects yet can also elicit serious treatment-related adverse events, such as liver toxicity, including in man. We engineered a variant that binds extracellular matrix through a super-affinity peptide derived from placenta growth factor-2 (PIGF-2(123-144)) to enhance anti-CD40's effects when administered locally. Peritumoral injection of PIGF-2(123-144)-anti-CD40 antibody showed prolonged tissue retention at the injection site and substantially decreased systemic exposure, resulting in decreased liver toxicity. In four mouse tumor models, PICF-2(123-144)-anti-CD40 antibody demonstrated enhanced antitumor efficacy compared with its unmodified form and correlated with activated dendritic cells, B cells, and 'T' cells in the tumor and in the tumor-draining lymph node. Moreover, in a genetically engineered Braf(V600E) beta Cat(STA )melanoma model that does not respond to checkpoint inhibitors, PIGF-2(123-144)-anti-CD40 antibody treatment enhanced T-cell infiltration into the tumors and slowed tumor growth. Together, these results demonstrate the marked therapeutic advantages of engineering matrix-binding domains onto agonistic anti-CD40 antibody as a therapeutic given by tumori-regional injection for cancer immunotherapy. (C) 2018 AACR.

AMER ASSOC CANCER RESEARCH2018

Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition

Christoph Schwärzler

Wiley2017