Targeting EP2 receptor with multifaceted mechanisms for high-risk neuroblastoma

Prostaglandin E2 (PGE2) promotes tumor cell proliferation, migration, and invasion, fostering an inflammation-enriched microenvironment that facilitates angiogenesis and immune evasion. However, the PGE2 receptor subtype (EP1–EP4) involved in neuroblastoma (NB) growth remains elusive. Herein, we show that the EP2 receptor highly correlates with NB aggressiveness and acts as a predominant Gαs-coupled receptor mediating PGE2-initiated cyclic AMP (cAMP) signaling in NB cells with high-risk factors, including 11q deletion and MYCN amplification. Knockout of EP2 in NB cells blocks the development of xenografts, and its conditional knockdown prevents established tumors from progressing. Pharmacological inhibition of EP2 by our recently developed antagonist TG6-129 suppresses the growth of NB xenografts in nude mice and syngeneic allografts in immunocompetent hosts, accompanied by anti-inflammatory, antiangiogenic, and apoptotic effects. This proof-of-concept study suggests that the PGE2/EP2 signaling pathway contributes to NB malignancy and that EP2 inhibition by our drug-like compounds provides a promising strategy to treat this deadly pediatric cancer. [Display omitted] •EP2 is a leading Gαs-coupled receptor for PGE2-initiated cAMP signaling in NB cells•Genetic deficiency of EP2 prevents the development and progression of high-risk NB•Treatment with our EP2 antagonist TG6-129 impairs NB with high-risk genetic factors•EP2 inhibition shows anti-inflammatory, antiangiogenic, and apoptotic effects in NB Hou et al. discover that prostaglandin receptor EP2 highly correlates with the aggressiveness of neuroblastoma, where it acts as the primary PGE2 receptor mediating cAMP signaling. EP2 deficiency or inhibition suppresses neuroblastoma with high-risk factors including 11q deletion and MYCN amplification, demonstrating EP2 as a promising therapeutic target for neuroblastoma.