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

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 () and Isabelle Coste ()
Additional contact information
François Virard: Centre Léon Bérard
Stéphane Giraud: Centre Léon Bérard
Mélanie Bonnet: Centre Léon Bérard
Léa Magadoux: Centre Léon Bérard
Laetitia Martin: Centre Léon Bérard
Thuy Ha Pham: Centre Léon Bérard
Najwa Skafi: Centre Léon Bérard
Sophie Deneuve: Centre Léon Bérard
Rita Frem: Centre Léon Bérard
Bruno O. Villoutreix: Hôpital Robert Debré
Nawal Hajj Sleiman: UMR 5242-CNRS/ENSL, Université Claude Bernard Lyon 1
Jonathan Reboulet: UMR 5242-CNRS/ENSL, Université Claude Bernard Lyon 1
Samir Merabet: UMR 5242-CNRS/ENSL, Université Claude Bernard Lyon 1
Vincent Chaptal: Molecular Microbiology and Structural Biochemistry Laboratory (CNRS UMR 5086), University of Lyon
Cédric Chaveroux: Centre Léon Bérard
Nader Hussein: Centre Léon Bérard
Nicolas Aznar: Centre Léon Bérard
Tanguy Fenouil: Centre Léon Bérard
Isabelle Treilleux: Centre Léon Bérard
Pierre Saintigny: Centre Léon Bérard
Stéphane Ansieau: Centre Léon Bérard
Serge Manié: Centre Léon Bérard
Serge Lebecque: Centre Léon Bérard
Toufic Renno: Centre Léon Bérard
Isabelle Coste: Centre Léon Bérard

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51275-z

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