Targeting non-canonical protein functions in cancer
Objectives
The team’s research aims to elucidate the molecular and cellular mechanisms linking inflammatory pathways to tumor development. Today, inflammation is considered one of the major hallmarks of cancer, as it promotes the various stages of tumorigenesis. Beyond the inflammatory response involving interactions between cancer cells and microenvironmental cells, the team focuses on studying these mechanisms within the cancer cell itself.
In this context, the protein MyD88 (Myeloid Differentiation primary response 88) plays a major role, positioned at the interface of signaling pathways involved in inflammation and tumor progression. MyD88 is an essential adaptor protein for signal transduction downstream of Toll-like, IL-1, and IL-18 receptors, and directly participates in the activation of pro-inflammatory and oncogenic programs. The team also demonstrated that MyD88 interacts with ERK, a crucial interaction for RAS-driven neoplastic transformation.
MyD88 thus represents an attractive therapeutic target. In this context, previous work by the team has shown that disrupting the interaction between MyD88 and ERK induces immunogenic cancer cell death. Our current projects aim to understand the molecular and structural mechanisms that regulate MyD88 activity and support its role in oncogenesis, in order to identify new therapeutic strategies.
Projects
- Role of post-translational modifications of MyD88: Structural approaches are used to characterize these modifications and understand their impact on the conformation and interactions of MyD88. In parallel, functional studies will assess how these modifications influence inflammatory signaling and cell transformation. The goal is to uncover new pathological mechanisms and identify vulnerabilities that can be exploited therapeutically.
- Impact of oncogenic MyD88 mutation on extra-nodal forms of B-cell lymphomas: The MyD88 L265P mutation, found in ~70% of extra-nodal large B-cell lymphomas, appears to contribute to this tropism. Our results suggest that embryonic transcription factors that were initially described to drive epithelial-to-mesenchymal transition may also promote the development of extra-nodal lymphomas. Our work aims to decipher the underlying molecular mechanisms.
- Inhibition of the ERK-MyD88 interaction: Our team has identified and validated this interaction as a therapeutic target in various tumor models, including lymphomas. Furthermore, its inhibition induces immunogenic cell death and effectively overcomes conventional resistance to targeted therapies. In collaboration with the team’s spinoff startup, TheraPPI, we are currently developing potent and selective inhibitors, using cutting-edge structural approaches (crystallography, NMR). These inhibitors will serve both as unique research tools and drug candidates in clinical settings.
By elucidating the mechanisms that regulate MyD88 activity and defining its critical alterations in cancer, our team is providing the scientific basis for translating these insights into new therapeutic opportunities in oncology.
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Toufic RENNO
toufic.renno@lyon.unicancer.fr+33 4 69 16 66 29
Centre Léon Bérard
Cheney D – 6th floor
28 rue Laennec
69008 Lyon
FranceIsabelle COSTE
isabelle.coste@lyon.unicancer.fr+33 4 69 16 66 30
Centre Léon Bérard
Cheney D – 6th floor
28 rue Laennec
69008 Lyon
France