In EGFR+ cells, MAPK, SK1 and S1P1 inhibitors made the cells sensitive to TMZ together with the ability of exogenously administered S1P to restore cell viability and resistance to TMZ, strongly indicating a crucial role of EGFRvIII and the downstream signaling ERK-SK1-S1P in the survival properties of EGFR+ GBM cells. Here, S1PR1 is linked to glioblastoma.