Combined PDE4+MEK inhibition shows antiproliferative effects in NRASQ61 mutated melanoma preclinical models.

Upregulation of phosphodiesterase type 4 (PDE4) has been associated with worse prognosis in several cancers. In melanomas harboring NRAS mutations, PDE4 upregulation has been shown to trigger a switch in signaling from BRAF to RAF1 which leads to mitogen-activated protein kinase pathway activation. Previous in vitro evidence showed that PDE4 inhibition induced death in NRASQ61mut melanoma cells and such a strategy may thus be a relevant therapeutic option in those cases with no molecular targeted therapies approved to date. In this study, we generated patient-derived xenografts (PDX) from two NRASQ61mut melanoma lesions. We performed ex vivo histoculture drug response assays and in vivo experiments. A significant ex vivo inhibition of proliferation with the combination of roflumilast+cobimetinib was observed compared to dimethyl sulfoxide control in both models (51 and 67%). This antiproliferative effect was confirmed in vivo for PDX-1 with a 56% inhibition of tumor growth. To decipher molecular mechanisms underlying this effect, we performed transcriptomic analyses and revealed a decrease in MKI67, RAF1 and CCND1 expression under bitherapy. Our findings strengthen the therapeutic interest of PDE4 inhibitors and support further experiments to evaluate this approach in metastatic melanoma. Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.

Citation

Baptiste Louveau, Coralie Reger De Moura, Fanélie Jouenne, Aurélie Sadoux, Clara Allayous, Laetitia Da Meda, Mélanie Bernard-Cacciarella, Barouyr Baroudjian, Céleste Lebbé, Samia Mourah, Nicolas Dumaz. Combined PDE4+MEK inhibition shows antiproliferative effects in NRASQ61 mutated melanoma preclinical models. Melanoma research. 2024 Apr 01;34(2):186-192

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PMID: 38141200

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