Oncogenic mutations drive anabolic metabolism, creating a dependency on nutrient influx through transporters, receptors, and macropinocytosis. While sphingolipids suppress tumor growth by downregulating nutrient transporters, macropinocytosis and autophagy still provide cancer cells with fuel. Therapeutics that simultaneously disrupt these parallel nutrient access pathways have potential as powerful starvation agents. Here, we describe a water-soluble, orally bioavailable synthetic sphingolipid, SH-BC-893, that triggers nutrient transporter internalization and also blocks lysosome-dependent nutrient generation pathways. SH-BC-893 activated protein phosphatase 2A (PP2A), leading to mislocalization of the lipid kinase PIKfyve. The concomitant mislocalization of the PIKfyve product PI(3,5)P2 triggered cytosolic vacuolation and blocked lysosomal fusion reactions essential for LDL, autophagosome, and macropinosome degradation. By simultaneously limiting access to both extracellular and intracellular nutrients, SH-BC-893 selectively killed cells expressing an activated form of the anabolic oncogene
Seong M. Kim, Saurabh G. Roy, Bin Chen, Tiffany M. Nguyen, Ryan J. McMonigle, Alison N. McCracken, Yanling Zhang, Satoshi Kofuji, Jue Hou, Elizabeth Selwan, Brendan T. Finicle, Tricia T. Nguyen, Archna Ravi, Manuel U. Ramirez, Tim Wiher, Garret G. Guenther, Mari Kono, Atsuo T. Sasaki, Lois S. Weisman, Eric O. Potma, Bruce J. Tromberg, Robert A. Edwards, Stephen Hanessian, Aimee L. Edinger
Vacuolating sphingolipid SH-BC-893 targets primary and adaptive pathways for nutrient acquisition.