title: Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma.
abstract: Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Shan
authors.initials: S
authors.lastname: Zhu
authors.forename: David
authors.initials: D
authors.lastname: Kozono
authors.forename: Kimberly
authors.initials: K
authors.lastname: Ng
authors.forename: Diahnn
authors.initials: D
authors.lastname: Futalan
authors.forename: Ying
authors.initials: Y
authors.lastname: Shen
authors.forename: Johnny C
authors.initials: JC
authors.lastname: Akers
authors.forename: Tyler
authors.initials: T
authors.lastname: Steed
authors.forename: Deepa
authors.initials: D
authors.lastname: Kushwaha
authors.forename: Michael
authors.initials: M
authors.lastname: Schlabach
authors.forename: Bob S
authors.initials: BS
authors.lastname: Carter
authors.forename: Chang-Hyuk
authors.initials: CH
authors.lastname: Kwon
authors.forename: Frank
authors.initials: F
authors.lastname: Furnari
authors.forename: Webster
authors.initials: W
authors.lastname: Cavenee
authors.forename: Stephen
authors.initials: S
authors.lastname: Elledge
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection
chemical_list: C581293:DRD2 protein, human; D034741:RNA, Small Interfering; D017448:Receptors, Dopamine D2; C512478:EGFR protein, human; D066246:ErbB Receptors