Reference Detail

Ref Type

Journal Article

PMID

(39574163)

Authors

Delyon J, Becherirat S, Roger A, Bernard-Cacciarella M, Reger De Moura C, Louveau B, Mourah S, Lebbé C, Dumaz N

Title

PDE4D drives rewiring of the MAPK pathway in BRAF-mutated melanoma resistant to MAPK inhibitors.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cell communication and signaling : CCS	22	1	2024 Nov 21	559	Cell Commun Signal

URL

Abstract Text

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

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Roflumilast	Roflumilast	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Roflumilast		B9302-107\|BY217\|BYK20869\|Daliresp\|Zoryve		Roflumilast inhibits PDE4D, potentially resulting in decreased tumor cell proliferation and reduced tumor growth (PMID: 39574163).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	melanoma	sensitive	Roflumilast + Vemurafenib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with the combination of Roflumilast and Zelboraf (vemurafenib) inhibited colony formation and resulted in decreased spheroid size of melanoma cells harboring BRAF V600E in culture, and led to greater inhibition of tumor growth in a cell line xenograft model compared to Zelboraf (vemurafenib) alone (PMID: 39574163).	39574163