A proteomic and phosphoproteomic landscape of KRAS mutant cancers identifies combination therapies.
Mol Cell
; 81(19): 4076-4090.e8, 2021 10 07.
Article
em En
| MEDLINE
| ID: mdl-34375582
ABSTRACT
KRAS mutant cancer, characterized by the activation of a plethora of phosphorylation signaling pathways, remains a major challenge for cancer therapy. Despite recent advancements, a comprehensive profile of the proteome and phosphoproteome is lacking. This study provides a proteomic and phosphoproteomic landscape of 43 KRAS mutant cancer cell lines across different tissue origins. By integrating transcriptomics, proteomics, and phosphoproteomics, we identify three subsets with distinct biological, clinical, and therapeutic characteristics. The integrative analysis of phosphoproteome and drug sensitivity information facilitates the identification of a set of drug combinations with therapeutic potentials. Among them, we demonstrate that the combination of DOT1L and SHP2 inhibitors is an effective treatment specific for subset 2 of KRAS mutant cancers, corresponding to a set of TCGA clinical tumors with the poorest prognosis. Together, this study provides a resource to better understand KRAS mutant cancer heterogeneity and identify new therapeutic possibilities.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfoproteínas
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Protocolos de Quimioterapia Combinada Antineoplásica
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Proteínas Proto-Oncogênicas p21(ras)
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Proteoma
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Proteômica
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Inibidores Enzimáticos
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Mutação
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Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Mol Cell
Assunto da revista:
BIOLOGIA MOLECULAR
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China