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

Autor: Delyon J; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France.; Université Paris Cité, AP-HP Dermato-oncology and CIC, Cancer institute APHP.nord Paris Cité, INSERM U976, Saint Louis Hospital, Paris, F-75010, France., Becherirat S; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France., Roger A; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France., Bernard-Cacciarella M; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France.; Université Paris Cité, AP-HP Dermato-oncology and CIC, Cancer institute APHP.nord Paris Cité, INSERM U976, Saint Louis Hospital, Paris, F-75010, France., Reger De Moura C; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France.; Department of Pharmacology and Tumor Genomics, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, F-75010, France., Louveau B; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France.; Department of Pharmacology and Tumor Genomics, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, F-75010, France., Mourah S; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France.; Department of Pharmacology and Tumor Genomics, Hôpital Saint Louis, Assistance Publique-Hôpitaux de Paris, Paris, F-75010, France., Lebbé C; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France.; Université Paris Cité, AP-HP Dermato-oncology and CIC, Cancer institute APHP.nord Paris Cité, INSERM U976, Saint Louis Hospital, Paris, F-75010, France., Dumaz N; Human Immunology Pathophysiology & Immunotherapy (HIPI), Université Paris Cité, INSERM U976 - Hôpital Saint Louis - 1 avenue Claude Vellefaux, Paris, 75010, France. nicolas.dumaz@inserm.fr.
Jazyk: angličtina
Zdroj: Cell communication and signaling : CCS [Cell Commun Signal] 2024 Nov 21; Vol. 22 (1), pp. 559. Date of Electronic Publication: 2024 Nov 21.
DOI: 10.1186/s12964-024-01941-y
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Competing Interests: Declarations. Ethics approval and consent to participate: The cohort of patients with unresectable advanced melanoma identified from the French prospective MELBASE biobank at Saint-Louis hospital, Paris, were included (ClinicalTrials.gov identifier: NCT02828202, CPP Ile-de-France XI, number 12027, 2012). All patients had provided written informed consent prior to enrollment. For melanoma cell xenograft experiments, animal housing, handling and all procedures involving mice were performed in accordance to Directive 2010/63/EU and all protocols were approved by the Committee on the Ethics of Animal Experiments of the French Ministry of Agriculture (Permit Number: APAFIS#11775-2017101316112852 v2). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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