Eltrombopag binds SDC4 directly and enhances MAPK signaling and macropinocytosis in cancer cells.

Syndecan-4 (SDC4) is a single-pass transmembrane glycoprotein implicated in a variety of oncogenic signaling pathways. It is also an intrinsically disordered protein and considered "undruggable". In the present study, we confirmed that knocking out SDC4 in pancreatic cancer cells markedly impaired macropinocytosis, colony formation, as well as xenograft tumor initiation and growth. Quantitative proteomic profiling of Sdc4 knockout (KO) cells revealed significant changes in cell metabolic pathways. In a cellular protein-based ligand interaction screening, we identified that Eltrombopag (ETBP), an FDA-approved agonist of the thrombopoietin receptor (TPOR) for immune thrombocytopenia, could directly bind to SDC4 with a Kd value of ~2 µM. We showed that the transmembrane motif was essential for SDC4 binding to ETBP. Unexpectedly, ETBP not only increased SDC4 abundance, but also enhanced SDC4-associated MAPK signaling pathway and macropinocytosis in cancer cells. Our results indicate that ETBP is a potential agonist of SDC4 in a fashion similar to its original target TPOR, and that caution should be taken when using ETBP for chemotherapy-induced thrombocytopenia in cancer patients. AJCR