PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors DOI Creative Commons
Julie Delyon,

Selma Becherirat,

Anissa Roger

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 21, 2024

Phosphodiesterase type 4D (PDE4D) breaks down cyclic AMP (cAMP) reducing the signaling of this intracellular second messenger which plays a major role in melanocyte pathophysiology. In advanced melanoma, expression PDE4D is increased, tumor invasion and negatively associated with survival. current work, we investigated resistance BRAF-mutated melanoma to mitogen-activated protein kinase (MAPK) pathway-targeted therapy. Established human cell line sensitive resistant BRAF MEK inhibitors tissues from patients were used study. Immunoblotting was analyze quantitative reverse transcription-PCR mRNA expression. DNA methylation analysis evaluated via bisulfite treatment followed by PCR. Cell viability measured clonogenic assays or spheroid cultures. xenograft experiments immunodeficient mice validate results vivo. Analysis baseline tumors BRAFV600E-mutated treated MAPK showed that higher situ predicted worse survival patients. Furthermore, acquired overexpression ex The PDE4D5 isoform cells targeted therapies explained demethylation deletion CpG island located upstream promoter. We further allowed RAF1 activation, promoting switch favoring inhibitors. As result, pharmacological inhibition PDE4 activity impeded proliferation vivo anti-tumorigenic inhibitor achieved Hippo pathway an important therapies. summary, our research drives rewiring suggests novel therapeutic option for

Language: Английский

PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors DOI Creative Commons
Julie Delyon,

Selma Becherirat,

Anissa Roger

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 21, 2024

Phosphodiesterase type 4D (PDE4D) breaks down cyclic AMP (cAMP) reducing the signaling of this intracellular second messenger which plays a major role in melanocyte pathophysiology. In advanced melanoma, expression PDE4D is increased, tumor invasion and negatively associated with survival. current work, we investigated resistance BRAF-mutated melanoma to mitogen-activated protein kinase (MAPK) pathway-targeted therapy. Established human cell line sensitive resistant BRAF MEK inhibitors tissues from patients were used study. Immunoblotting was analyze quantitative reverse transcription-PCR mRNA expression. DNA methylation analysis evaluated via bisulfite treatment followed by PCR. Cell viability measured clonogenic assays or spheroid cultures. xenograft experiments immunodeficient mice validate results vivo. Analysis baseline tumors BRAFV600E-mutated treated MAPK showed that higher situ predicted worse survival patients. Furthermore, acquired overexpression ex The PDE4D5 isoform cells targeted therapies explained demethylation deletion CpG island located upstream promoter. We further allowed RAF1 activation, promoting switch favoring inhibitors. As result, pharmacological inhibition PDE4 activity impeded proliferation vivo anti-tumorigenic inhibitor achieved Hippo pathway an important therapies. summary, our research drives rewiring suggests novel therapeutic option for

Language: Английский

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