BRAF and MEK inhibitor combinations induce potent molecular and immunological effects in NRAS-mutant melanoma cells: Insights into mode of action and resistance mechanisms.
BRAF
MEK
NRAS mutation
melanoma
resistance
Journal
International journal of cancer
ISSN: 1097-0215
Titre abrégé: Int J Cancer
Pays: United States
ID NLM: 0042124
Informations de publication
Date de publication:
11 Dec 2023
11 Dec 2023
Historique:
revised:
17
10
2023
received:
18
01
2023
accepted:
03
11
2023
medline:
11
12
2023
pubmed:
11
12
2023
entrez:
11
12
2023
Statut:
aheadofprint
Résumé
About 25% of melanoma harbor activating NRAS mutations, which are associated with aggressive disease therefore requiring a rapid antitumor intervention. However, no efficient targeted therapy options are currently available for patients with NRAS-mutant melanoma. MEK inhibitors (MEKi) appear to display a moderate antitumor activity and also immunological effects in NRAS-mutant melanoma, providing an ideal backbone for combination treatments. In our study, the MEKi binimetinib, cobimetinib and trametinib combined with the BRAF inhibitors (BRAFi) encorafenib, vemurafenib and dabrafenib were investigated for their ability to inhibit proliferation, induce apoptosis and alter the expression of immune modulatory molecules in sensitive NRAS-mutant melanoma cells using two- and three-dimensional cell culture models as well as RNA sequencing analyses. Furthermore, NRAS-mutant melanoma cells resistant to the three BRAFi/MEKi combinations were established to characterize the mechanisms contributing to their resistance. All BRAFi induced a stress response in the sensitive NRAS-mutant melanoma cells thereby significantly enhancing the antiproliferative and proapoptotic activity of the MEKi analyzed. Furthermore, BRAFi/MEKi combinations upregulated immune relevant molecules, such as ICOS-L, components of antigen-presenting machinery and the "don't eat me signal" molecule CD47 in the melanoma cells. The BRAFi/MEKi-resistant, NRAS-mutant melanoma cells counteracted the molecular and immunological effects of BRAFi/MEKi by upregulating downstream mitogen-activated protein kinase pathway molecules, inhibiting apoptosis and promoting immune escape mechanisms. Together, our study reveals potent molecular and immunological effects of BRAFi/MEKi in sensitive NRAS-mutant melanoma cells that may be exploited in new combinational treatment strategies for patients with NRAS-mutant melanoma.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Bundesministerium für Bildung und Forschung
ID : 01ZX1913A
Organisme : Bundesministerium für Bildung und Forschung
ID : 01ZX1913C
Organisme : Deutsche Forschungsgemeinschaft
ID : SE 581/33-1
Organisme : Deutsche Forschungsgemeinschaft
ID : SE 581/34-1
Organisme : Deutsche Krebshilfe
ID : 70113450
Organisme : Else Kröner-Fresenius-Stiftung
Organisme : NCT Scholarship for Medical Doctoral Thesis
Informations de copyright
© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.
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