Targeting ERK-MYD88 interaction leads to ERK dysregulation and immunogenic cancer cell death
Year: 2024
Type: article
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. The interaction between MyD88 and ERK is necessary for RAS-dependent transformation and cancer cell survival. Here, the authors identify benzimidazole compound EI-52 as a disrupter of this interaction and demonstrate its therapeutic efficacy in tumours via ERK dysregulation and the induction of immunogenic cell death.
Source: Nature Communications
Authors: François Virard, Stéphane Giraud, Mélanie Bonnet, Léa Magadoux, Laetitia Martin, Thuy Ha Pham, Najwa Skafi, Sophie Deneuve, Rita Frem, Bruno O. Villoutreix, Nawal Hajj Sleiman, Jonathan Reboulet, Samir Merabet, Vincent Chaptal, Cédric Chaveroux, Nader Hussein, Nicolas Aznar, Tanguy Fenouil, Isabelle Treilleux, Pierre Saintigny, Stéphane Ansieau, Serge Manié, Serge Lebecque, Toufic Renno, Isabelle Coste
Institutions: Centre National de la Recherche Scientifique, Inserm, Hospices Civils de Lyon, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Université Paris Cité, Hôpital Robert-Debré, NeuroDiderot, Lyon 1 Université, École Normale Supérieure de Lyon, Institut de Génomique Fonctionnelle de Lyon, Université de Lyon, Microbiologie moléculaire et biochimie structurale
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,790
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
OpenAlex ID: W4401612322