Novel treatment strategy for NRAS-mutated melanoma through a selective inhibitor of CD147/VEGFR-2 interaction

Landras, Alexandra; Moura, Coralie Reger de; Villoutreix, Bruno O.; Battistella, Maxime; Sadoux, Aurélie; Dumaz, Nicolas; Ménashi, Suzanne; Fernández‐Recio, Juan; Lebbe, Célèste

doi:10.1038/s41388-022-02244-7

Cited by 5 publications

(4 citation statements)

References 52 publications

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“…Mouse experiments were conducted as previously described [9][10][11] and were approved by the Committee on the Ethics of Animal Experiments of the French Ministry of Agriculture (Permit Number: B751008-22952). After 1 week of acclimatization, female 5-week-old NSG (NOD SCID Gamma) mice were xenografted with patient-derived melanoma tissues.…”

Section: Animal Experiments and Xenograft-derived Histoculture Drug R...mentioning

confidence: 99%

Combined PDE4+MEK inhibition shows antiproliferative effects in NRAS Q61 mutated melanoma preclinical models

Louveau,

Reger De Moura,

Jouenne

et al. 2023

Melanoma Research

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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 NRAS Q61mut 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 NRAS Q61mut 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 sulfoxyde 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.

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Section: Animal Experiments and Xenograft-derived Histoculture Drug R...mentioning

confidence: 99%

Combined PDE4+MEK inhibition shows antiproliferative effects in NRAS Q61 mutated melanoma preclinical models

Louveau,

Reger De Moura,

Jouenne

et al. 2023

Melanoma Research

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“…Furthermore, CD147/VEGFR-2 peptide inhibitor reduced malignant potential through the STAT3 pathway and resensitized MEKi-resistant NRAS-mutant xenografts to MEKi. The MEKi-CD147i combination induced tumor regression in PDX [ 27 ]. These strategies, though in their early phase of investigation, may help overcome resistance and enhance the efficacy of inhibitors targeting the MAPK pathway.…”

Section: Nrasmentioning

confidence: 99%

Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies

Rager

Eckburg

Patel

et al. 2022

Cancers

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Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.

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“…The NRAS is one of the first genes shown to be mutated explicitly in GIMM, which occurs in about a fifth of cutaneous melanoma and imposes a high-level aggressive clinical behaviour and the burden of GIMM has increased remarkably in recent years [ 25 , 26 , 27 ]. A growing of literature has documented that the NRAS mutation is substantially related to a higher incidence of melanoma (i.e., 15–30% of melanoma) [ 27 ], which is ten times higher than repeatedly than HRAS or KRAS [ 20 , 28 , 29 ]. NRAS mutations transforming all three genes to involve oncogenes almost continuously happen in residues 12, 13, or 51 of the protein [ 30 , 31 ].…”

Section: The Potential Key Players In Genetic Instability and Mutatio...mentioning

confidence: 99%

The Emerging Burden of Genetic Instability and Mutation in Melanoma: Role of Molecular Mechanisms

Mahumud

Shahjalal

2022

Cancers

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Melanoma is a severe skin cancer affecting thousands of people and a growing public health concern worldwide. The potential hallmarks of melanoma are genetic instability and mutation (GIAM), which are driving mechanisms for phenotypic variation and adaptation in melanoma. In metastatic melanoma, DNA repair-associated genes are frequently expressed at higher levels than in primary cancers, suggesting melanoma cells rely on genetic stability to spread distantly. The tumour microenvironment is affected by genomic instability and melanoma mutation (GIMM), which plays significant roles in developing GIMM and their contributions to the overall disease burden. The GIAM is the crucial vulnerability of cancer cells, determining their sensitivity to harmful treatments, including radiation and many chemotherapeutics. The high incidence of melanoma is typically associated with genetic modifications, and several clinical and genetic interventions have been critical in easing the burden.

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Novel treatment strategy for NRAS-mutated melanoma through a selective inhibitor of CD147/VEGFR-2 interaction

Cited by 5 publications

References 52 publications

Combined PDE4+MEK inhibition shows antiproliferative effects in NRAS Q61 mutated melanoma preclinical models

Combined PDE4+MEK inhibition shows antiproliferative effects in NRAS Q61 mutated melanoma preclinical models

Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies

The Emerging Burden of Genetic Instability and Mutation in Melanoma: Role of Molecular Mechanisms

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