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.