Priority Research Papers:
Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma
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Jie Li1,*, Shan Zhu2,*, David Kozono2,*, Kimberly Ng1, Diahnn Futalan1, Ying Shen1, Johnny C. Akers1, Tyler Steed1, Deepa Kushwaha2, Michael Schlabach3, Bob S. Carter1, Chang-Hyuk Kwon4, Frank Furnari5, Webster Cavenee5, Stephen Elledge6, Clark C. Chen1
1 Center for Translational and Applied Neuro-oncology, Division of Neurosurgery, University of California, San Diego, CA
2 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
3 Novartis Institutes for BioMedical Research, Cambridge, MA
4 Department of Neurological Surgery and Solid Tumor Program, Ohio State University Medical Center, Columbus, OH
5 Ludwig Institute for Cancer Research, La Jolla, CA
6 Department of Genetics, Harvard Medical School, Boston, MA
* Equal contribution
Clark C. Chen, email:
Keywords: Glioblastoma, DRD2, EGFR, mitogenic signaling
Received: February 11, 2014 Accepted: March 6, 2014 Published: March 7, 2014
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.
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