Figure 1. Targeting synergistic dependency on MAPK and dopamine signaling in glioblastoma.

Canonical pro-survival and mitogenic MAPK signaling, commonly deregulated in glioblastoma, is depicted as a simplified signaling cascade of EGFR, Ras-GTP and MAPK kinases Erk1 and Erk2 (Erk1/2). At the Ras node, MAPK pathway is positively modulated by dopamine signaling. Upon ligand binding, the DRD2 receptor holds inactive small GTPase Rap1 through activation of heterotrimeric G protein alpha i2 (alpha/beta/gamma) and the GTPase-activating protein RAP (RAP-GAPII), which promote GDP-bound (inactive) Rap1. Rap1 is a Ras antagonist and its inactivation thus results in amplification of MAPK signaling. Therefore, combined targeting of both pathways can offer a promising strategy for glioblastoma therapy.