A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer.
Cell
; 162(1): 146-59, 2015 Jul 02.
Article
en En
| MEDLINE
| ID: mdl-26140595
ABSTRACT
KRAS is one of the most frequently mutated oncogenes in human cancer. Despite substantial efforts, no clinically applicable strategy has yet been developed to effectively treat KRAS-mutant tumors. Here, we perform a cell-line-based screen and identify strong synergistic interactions between cell-cycle checkpoint-abrogating Chk1- and MK2 inhibitors, specifically in KRAS- and BRAF-driven cells. Mechanistically, we show that KRAS-mutant cancer displays intrinsic genotoxic stress, leading to tonic Chk1- and MK2 activity. We demonstrate that simultaneous Chk1- and MK2 inhibition leads to mitotic catastrophe in KRAS-mutant cells. This actionable synergistic interaction is validated using xenograft models, as well as distinct Kras- or Braf-driven autochthonous murine cancer models. Lastly, we show that combined checkpoint inhibition induces apoptotic cell death in KRAS- or BRAF-mutant tumor cells directly isolated from patients. These results strongly recommend simultaneous Chk1- and MK2 inhibition as a therapeutic strategy for the treatment of KRAS- or BRAF-driven cancers.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas
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Adenocarcinoma
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Proteínas Proto-Oncogénicas
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Proteínas Serina-Treonina Quinasas
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Apoptosis
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Proteínas ras
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Péptidos y Proteínas de Señalización Intracelular
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Sinergismo Farmacológico
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Inhibidores Enzimáticos
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Antineoplásicos
Límite:
Animals
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Humans
Idioma:
En
Año:
2015
Tipo del documento:
Article