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Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death.
Virard, François; Giraud, Stéphane; Bonnet, Mélanie; Magadoux, Léa; Martin, Laetitia; Pham, Thuy Ha; Skafi, Najwa; Deneuve, Sophie; Frem, Rita; Villoutreix, Bruno O; Sleiman, Nawal Hajj; Reboulet, Jonathan; Merabet, Samir; Chaptal, Vincent; Chaveroux, Cédric; Hussein, Nader; Aznar, Nicolas; Fenouil, Tanguy; Treilleux, Isabelle; Saintigny, Pierre; Ansieau, Stéphane; Manié, Serge; Lebecque, Serge; Renno, Toufic; Coste, Isabelle.
Afiliação
  • Virard F; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Giraud S; University of Lyon, Faculté d'Odontologie, Hospices Civils de Lyon, Lyon, France.
  • Bonnet M; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Magadoux L; Center for Drug Discovery and Development, Synergy Lyon Cancer Foundation, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Martin L; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Pham TH; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Skafi N; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Deneuve S; Center for Drug Discovery and Development, Synergy Lyon Cancer Foundation, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Frem R; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Villoutreix BO; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Sleiman NH; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Reboulet J; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Merabet S; Université de Paris, NeuroDiderot, Inserm, Hôpital Robert Debré, 75019, Paris, France.
  • Chaptal V; Institut de Génomique Fonctionnelle de Lyon, UMR 5242-CNRS/ENSL, Université Claude Bernard Lyon 1, Lyon, France.
  • Chaveroux C; Institut de Génomique Fonctionnelle de Lyon, UMR 5242-CNRS/ENSL, Université Claude Bernard Lyon 1, Lyon, France.
  • Hussein N; Institut de Génomique Fonctionnelle de Lyon, UMR 5242-CNRS/ENSL, Université Claude Bernard Lyon 1, Lyon, France.
  • Aznar N; Drug Resistance & Membrane Proteins group, Molecular Microbiology and Structural Biochemistry Laboratory (CNRS UMR 5086), University of Lyon, Lyon, France.
  • Fenouil T; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Treilleux I; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Saintigny P; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Ansieau S; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Manié S; University of Lyon, Faculté de Médecine, Hospices Civils de Lyon, Lyon, France.
  • Lebecque S; Pathology Department, Centre Léon Bérard, Lyon, France.
  • Renno T; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • Coste I; University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
Nat Commun ; 15(1): 7037, 2024 Aug 15.
Article em En | MEDLINE | ID: mdl-39147750
ABSTRACT
The quest for targeted therapies is critical in the battle against cancer. The RAS/MAP kinase pathway is frequently implicated in neoplasia, with ERK playing a crucial role as the most distal kinase in the RAS signaling cascade. Our previous research demonstrated that the interaction between ERK and MYD88, an adaptor protein in innate immunity, is crucial for RAS-dependent transformation and cancer cell survival. In this study, we examine the biological consequences of disrupting the ERK-MYD88 interaction through the ERK D-recruitment site (DRS), while preserving ERK's kinase activity. Our results indicate that EI-52, a small-molecule benzimidazole targeting ERK-MYD88 interaction induces an HRI-mediated integrated stress response (ISR), resulting in immunogenic apoptosis specific to cancer cells. Additionally, EI-52 exhibits anti-tumor efficacy in patient-derived tumors and induces an anti-tumor T cell response in mice in vivo. These findings suggest that inhibiting the ERK-MYD88 interaction may be a promising therapeutic approach in cancer treatment.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzimidazóis / MAP Quinases Reguladas por Sinal Extracelular / Fator 88 de Diferenciação Mieloide Limite: Animals / Female / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: França País de publicação: Reino Unido

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Benzimidazóis / MAP Quinases Reguladas por Sinal Extracelular / Fator 88 de Diferenciação Mieloide Limite: Animals / Female / Humans Idioma: En Revista: Nat Commun Assunto da revista: BIOLOGIA / CIENCIA Ano de publicação: 2024 Tipo de documento: Article País de afiliação: França País de publicação: Reino Unido