Non-canonical signaling hubs upon inhibition of MyD88-ERK interaction in cancer
Abstract
The RAS-MAPK pathway is frequently dysregulated in cancer, leading to malignant transformation. We previously identified a direct interaction between MyD88, a central adaptor of inflammatory signaling, and ERK, the terminal kinase of the RAS-MAPK cascade. Pharmacologic disruption of this ERK-MyD88 complex with a small molecule induces immunogenic cell death and antitumor immunity, suggesting a novel therapeutic strategy. Here, we show that ERK-MyD88 inhibition drives cellular signaling from non-canonical hubs. First, ERK-MyD88 disruption activates an integrated stress response that drives caspase-8-dependent apoptosis through a FADD-independent pathway within p62-ubiquitin aggregates. Second, it promotes assembly of MyD88, IRAK1, and IRAK4 into Myddosomes that produce proinflammatory chemokines independently of TLR or IL-1R activation. These findings demonstrate that perturbation of the ERK-MyD88 complex rewires cellular signaling into cell-autonomous hubs that coordinate caspase activation with chemokine secretion, thereby driving a program of immunogenic cancer cell death.
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BibTeX
@article{hussein2026noncanonical,
title = {{Non-canonical signaling hubs upon inhibition of MyD88-ERK interaction in cancer}},
author = {Nader Hussein and Najwa Skafi and Thuy Ha Pham and Melina Gautier and Francois Virard and Frédérique Fauvet and Léa Magadoux and Christelle Chassot-Lamblot and Anne-Pierre Morel and Christophe Vanbelle and Bassam Badran and Serge Lebecque and Serge Nicolas Manié and Sylvain Lamure and Toufic Renno and Isabelle Coste},
journal = {Cell Death and Disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09131-z},
url = {https://hal.science/hal-05767899v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Non-canonical signaling hubs upon inhibition of MyD88-ERK interaction in cancer
AU - Nader Hussein
AU - Najwa Skafi
AU - Thuy Ha Pham
AU - Melina Gautier
AU - Francois Virard
AU - Frédérique Fauvet
AU - Léa Magadoux
AU - Christelle Chassot-Lamblot
AU - Anne-Pierre Morel
AU - Christophe Vanbelle
AU - Bassam Badran
AU - Serge Lebecque
AU - Serge Nicolas Manié
AU - Sylvain Lamure
AU - Toufic Renno
AU - Isabelle Coste
PY - 2026
DA - 2026/07/30
JO - Cell Death and Disease
DO - 10.1038/s41419-026-09131-z
UR - https://hal.science/hal-05767899v1
AB - The RAS-MAPK pathway is frequently dysregulated in cancer, leading to malignant transformation. We previously identified a direct interaction between MyD88, a central adaptor of inflammatory signaling, and ERK, the terminal kinase of the RAS-MAPK cascade. Pharmacologic disruption of this ERK-MyD88 complex with a small molecule induces immunogenic cell death and antitumor immunity, suggesting a novel therapeutic strategy. Here, we show that ERK-MyD88 inhibition drives cellular signaling from non-canonical hubs. First, ERK-MyD88 disruption activates an integrated stress response that drives caspase-8-dependent apoptosis through a FADD-independent pathway within p62-ubiquitin aggregates. Second, it promotes assembly of MyD88, IRAK1, and IRAK4 into Myddosomes that produce proinflammatory chemokines independently of TLR or IL-1R activation. These findings demonstrate that perturbation of the ERK-MyD88 complex rewires cellular signaling into cell-autonomous hubs that coordinate caspase activation with chemokine secretion, thereby driving a program of immunogenic cancer cell death.
SN - 2041-4889
ER -