Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death
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.
Authors
- Nawal Hajj Sleiman (ORCID: https://orcid.org/0000-0002-0385-543X)
- Serge N. Manié (ORCID: https://orcid.org/0000-0002-9168-1977)
- Isabelle Coste (ORCID: https://orcid.org/0000-0002-9820-4452)
- Thuy Ha Pham (ORCID: https://orcid.org/0009-0005-3568-6633)
- Najwa Skafi (ORCID: https://orcid.org/0000-0002-0924-6168)
- Vincent Chaptal (ORCID: https://orcid.org/0000-0003-2603-0294)
- Tanguy Fenouil (ORCID: https://orcid.org/0000-0002-2747-763X)
- Serge Lebecque (ORCID: https://orcid.org/0000-0003-4006-8061)
- Jonathan Reboulet (ORCID: https://orcid.org/0000-0003-4867-9844)
- Laetitia B. B. Martin (ORCID: https://orcid.org/0000-0002-6921-7246)
- François Virard (ORCID: https://orcid.org/0000-0001-7570-1088)
- Bruno O. Villoutreix (ORCID: https://orcid.org/0000-0002-6456-7730)
- Sophie Deneuve (ORCID: https://orcid.org/0000-0001-7044-7869)
- Pierre Saintigny (ORCID: https://orcid.org/0000-0002-8090-9323)
- Léa Magadoux
- Cédric Chaveroux (ORCID: https://orcid.org/0000-0002-4116-3354)
- Stéphane Ansieau (ORCID: https://orcid.org/0000-0003-0989-2108)
- Samir Merabet (ORCID: https://orcid.org/0000-0001-7629-703X)
- Nicolas Aznar (ORCID: https://orcid.org/0000-0003-3338-9932)
- Rita Frem (ORCID: https://orcid.org/0000-0001-5288-3683)
- Isabelle Treilleux (ORCID: https://orcid.org/0000-0003-3919-5506)
- Toufic Renno (ORCID: https://orcid.org/0000-0001-6889-2920)
- Mélanie Bonnet
- Stéphane Giraud
- Nader Hussein
Institutions
- Université Claude Bernard Lyon 1 (FR)
- École Normale Supérieure de Lyon (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Paris Cité (FR)
- Centre de Biologie du Développement (FR)
- Hospices Civils de Lyon (FR)
- Laboratoire de Biologie Structurale de la Cellule (FR)
- Centre Léon Bérard (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Institut de Génomique Fonctionnelle de Lyon (FR)
- Hôpital Robert-Debré (FR)
- NeuroDiderot (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1038/s41467-024-51275-z
- Citations
- 8
- Primary Topic
- Melanoma and MAPK Pathways
- Type
- article
- Field-Weighted Citation Impact
- 1.87
Funders
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Fondation ARC pour la Recherche sur le Cancer
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique
- Institut National Du Cancer
- Direction Générale de l’offre de Soins
- Université de Lyon
- Pulsalys
- Centre Léon Bérard