Metabolic Adaptations to MEK and CDK4/6 Cotargeting in Uveal Melanoma.
Mol Cancer Ther
; 19(8): 1719-1726, 2020 08.
Article
em En
| MEDLINE
| ID: mdl-32430489
ABSTRACT
Frequent GNAQ and GNA11 mutations in uveal melanoma hyperactivate the MEK-ERK signaling pathway, leading to aberrant regulation of cyclin-dependent kinases (CDK) and cell-cycle progression. MEK inhibitors (MEKi) alone show poor efficacy in uveal melanoma, raising the question of whether downstream targets can be vertically inhibited to provide long-term benefit. CDK4/6 selective inhibitors are FDA-approved in patients with estrogen receptor (ER)-positive breast cancer in combination with ER antagonists/aromatase inhibitors. We determined the effects of MEKi plus CDK4/6 inhibitors (CDK4/6i) in uveal melanoma. In vitro, palbociclib, a CDK4/6i, enhanced the effects of MEKi via downregulation of cell-cycle proteins. In contrast, in vivo CDK4/6 inhibition alone led to cytostasis and was as effective as MEKi plus CDK4/6i treatment at delaying tumor growth. RNA sequencing revealed upregulation of the oxidative phosphorylation (OxPhos) pathway in both MEKi-resistant tumors and CDK4/6i-tolerant tumors. Furthermore, oxygen consumption rate was increased following MEKi + CDK4/6i treatment. IACS-010759, an OxPhos inhibitor, decreased uveal melanoma cell survival in combination with MEKi + CDK4/6i. These data highlight adaptive upregulation of OxPhos in response to MEKi + CDK4/6i treatment in uveal melanoma and suggest that suppression of this metabolic state may improve the efficacy of MEKi plus CDK4/6i combinations.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Uveais
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Regulação Neoplásica da Expressão Gênica
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MAP Quinase Quinase 1
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Inibidores de Proteínas Quinases
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Quinase 4 Dependente de Ciclina
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Quinase 6 Dependente de Ciclina
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Transcriptoma
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Melanoma
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Mol Cancer Ther
Ano de publicação:
2020
Tipo de documento:
Article