Here, using a combination of transcriptomics, proteomics, multiplex spatial profiling as well as in vitro and in vivo functional assays, we show that JAK/STAT3 activity is upregulated following selumetinib treatment in SHH MB tumor xenografts and that targeting this pathway, in combination with MEK inhibition, significantly attenuates tumor growth. The gene discussed is STAT3; the disease is neoplasm.