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

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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, Cedric | Hussein, Nader | Aznar, N | Fenouil, Tanguy | Treilleux, Isabelle | Saintigny, Pierre | Ansieau, Stéphane | Manié, Serge | Lebecque, Serge | Renno, Toufic | Coste, Isabelle

Edité par CCSD ; Nature Publishing Group -

International audience. 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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