Preclinical activity of cobimetinib alone or in combination with chemotherapy and targeted therapies in renal cell carcinoma.
Future Oncol
; 17(23): 3051-3060, 2021 Aug.
Article
em En
| MEDLINE
| ID: mdl-33906367
ABSTRACT
Background:
The poor outcome of advanced renal cell carcinoma (RCC) necessitates new treatments. Cobimetinib is a MEK inhibitor and approved for the treatment of melanoma. This work investigated the efficacy of cobimetinib alone and in combination with anti-RCC drugs.Methods:
Proliferation and apoptosis assays were performed, and combination index was analyzed on RCC cell lines (CaKi-2, 786-O, A-704, ACHN and A489) and xenograft models. Immunoblotting analysis was conducted to investigate the MAPK pathway.Results:
Cobimetinib was active against RCC cells, with IC50 at 0.006-0.8µM, and acted synergistically with standard-of-care therapy. Cobimetinib at nontoxic doses prevented tumor formation, inhibited tumor growth and enhanced efficacy of 5-fluorouracil, sorafenib and sunitinib via suppressing Raf/MEK/ERK, leading to MAPK pathway inhibition.Conclusion:
Our findings demonstrate the potent anti-RCC activity of cobimetinib and its synergism with RCC standard-of-care drugs, and confirm the underlying mechanism of the action of cobimetinib.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Piperidinas
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Azetidinas
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Carcinoma de Células Renais
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Protocolos de Quimioterapia Combinada Antineoplásica
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Inibidores de Proteínas Quinases
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Neoplasias Renais
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article