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GCN2 is a determinant of the response to WEE1 kinase inhibition in small-cell lung cancer.
Drainas, Alexandros P; Hsu, Wen-Hao; Dallas, Alec E; Poltorack, Carson D; Kim, Jun W; He, Andy; Coles, Garry L; Baron, Maya; Bassik, Michael C; Sage, Julien.
Afiliação
  • Drainas AP; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Hsu WH; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Dallas AE; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Poltorack CD; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Kim JW; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • He A; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Coles GL; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Baron M; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Bassik MC; Department of Genetics, Stanford University, Stanford, CA, USA.
  • Sage J; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Genetics, Stanford University, Stanford, CA, USA. Electronic address: julsage@stanford.edu.
Cell Rep ; 43(8): 114606, 2024 Aug 27.
Article em En | MEDLINE | ID: mdl-39120974
ABSTRACT
Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a dependency on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M checkpoint kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here, using CRISPR-Cas9 knockout screens in vitro and in vivo, we identified multiple factors influencing the response of SCLC cells to the WEE1 kinase inhibitor AZD1775, including the GCN2 kinase and other members of its signaling pathway. Rapid activation of GCN2 upon AZD1775 treatment triggers a stress response in SCLC cells. Pharmacological or genetic activation of the GCN2 pathway enhances cancer cell killing by AZD1775. Thus, activation of the GCN2 pathway represents a promising strategy to increase the efficacy of WEE1 inhibitors in SCLC.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinonas / Proteínas Tirosina Quinases / Proteínas Serina-Treonina Quinases / Proteínas de Ciclo Celular / Inibidores de Proteínas Quinases / Carcinoma de Pequenas Células do Pulmão / Neoplasias Pulmonares Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pirimidinonas / Proteínas Tirosina Quinases / Proteínas Serina-Treonina Quinases / Proteínas de Ciclo Celular / Inibidores de Proteínas Quinases / Carcinoma de Pequenas Células do Pulmão / Neoplasias Pulmonares Limite: Animals / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos