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<p>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.</p>

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Non-canonical signaling hubs upon inhibition of MyD88-ERK interaction in cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月30日

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  • Nader Hussein,
  • Najwa Skafi,
  • Thuy Ha Pham,
  • Melina Gautier,
  • Francois Virard,
  • Frédérique Fauvet,
  • Léa Magadoux,
  • Christelle Chassot-Lamblot,
  • Anne-Pierre Morel,
  • Christophe Vanbelle,
  • Bassam Badran,
  • Serge Lebecque,
  • Serge Nicolas Manié,
  • Sylvain Lamure,
  • Toufic Renno,
  • Isabelle Coste

摘要

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.