Silencing of SPRY1 triggers complete regression of rhabdomyosarcoma tumors carrying a mutated RAS gene.
RAS oncogenes are among the most frequently mutated genes in human cancer, but effective strategies for therapeutic inhibition of the RAS pathway have been elusive. Sprouty1 (SPRY1) is an upstream antagonist of RAS that is activated by extracellular signal-related kinase (ERK), providing a negative feedback loop for RAS signaling, and other evidence suggests that SPRY1 may have a tumor suppressor function. Studies of RAS status in the human childhood tumor rhabdomyosarcoma (RMS) indicated mutations in approximately half of the tumors of the embryonal rhabdomyosarcoma subtype (ERMS) but not the alveolar subtype (ARMS). ERMS tumors also showed overexpression of SPRY1, which was indeed upregulated by mutant RAS. However, we found that, in the presence of mutant RAS, the function of SPRY1 was changed from an antagonist to an agonist of RAS signaling. Thus, SPRY1 supported formation of activated ERK and mitogen-activated protein/ERK kinase and was essential for ERMS cell proliferation and survival. Conversely, silencing of SPRY1 in ERMS cells (but not ARMS cells) abolished their tumorigenicity in mice. Moreover, silencing of SPRY1 caused regression of established ERMS tumors (but not ARMS tumors) formed in xenograft settings. Our findings argue that SPRY1 inhibition can offer a therapeutic strategy to treat childhood RMS and possibly other tumors carrying oncogenic RAS mutations.
Schaaf
Gerben
G
Department of Human Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
Hamdi
Mohamed
M
Zwijnenburg
Danny
D
Lakeman
Arjan
A
Geerts
Dirk
D
Versteeg
Rogier
R
Kool
Marcel
M
D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009154:Mutation; D041681:NIH 3T3 Cells; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics*; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000378:metabolism; D018233:Rhabdomyosarcoma, Embryonal / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D008565:Membrane Proteins; D010750:Phosphoproteins; C486055:SPRY1 protein, human; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins