2. Academic Validation
  3. Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death

Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death

  • Nat Commun. 2024 Aug 15;15(1):7037. doi: 10.1038/s41467-024-51275-z.
François Virard 1 2,  Stéphane Giraud 1 3,  Mélanie Bonnet 1,  Léa Magadoux 1,  Laetitia Martin 1 3,  Thuy Ha Pham 1,  Najwa Skafi 1,  Sophie Deneuve 1,  Rita Frem 1,  Bruno O Villoutreix 4,  Nawal Hajj Sleiman 5,  Jonathan Reboulet 5,  Samir Merabet 5,  Vincent Chaptal 6,  Cédric Chaveroux 1,  Nader Hussein 1,  Nicolas Aznar 1,  Tanguy Fenouil 1 7,  Isabelle Treilleux 8,  Pierre Saintigny 1,  Stéphane Ansieau 1,  Serge Manié 1,  Serge Lebecque 1 7,  Toufic Renno # 9,  Isabelle Coste # 10
Affiliations

Affiliations

  • 1 University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • 2 University of Lyon, Faculté d'Odontologie, Hospices Civils de Lyon, Lyon, France.
  • 3 Center for Drug Discovery and Development, Synergy Lyon Cancer Foundation, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France.
  • 4 Université de Paris, NeuroDiderot, Inserm, Hôpital Robert Debré, 75019, Paris, France.
  • 5 Institut de Génomique Fonctionnelle de Lyon, UMR 5242-CNRS/ENSL, Université Claude Bernard Lyon 1, Lyon, France.
  • 6 Drug Resistance & Membrane Proteins group, Molecular Microbiology and Structural Biochemistry Laboratory (CNRS UMR 5086), University of Lyon, Lyon, France.
  • 7 University of Lyon, Faculté de Médecine, Hospices Civils de Lyon, Lyon, France.
  • 8 Pathology Department, Centre Léon Bérard, Lyon, France.
  • 9 University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France. toufic.renno@lyon.unicancer.fr.
  • 10 University Claude Bernard Lyon 1, INSERM U1052-CNRS UMR5286, Lyon Cancer Research Center, Centre Léon Bérard, Lyon, France. isabelle.coste@lyon.unicancer.fr.
  • # Contributed equally.
PMID: 39147750 DOI: 10.1038/s41467-024-51275-z
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.

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