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Sci Signal. 2018 Sep 11;11(547). pii: eaau5147. doi: 10.1126/scisignal.aau5147.

Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma.

Author information

1
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. mscott@stanford.edu tpurzner@stanford.edu.
2
Division of Neurosurgery, University of Toronto, Toronto, Ontario M5S1A1, Canada.
3
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Department of Molecular Medicine, University of Padua, Padova, PD 35122, Italy.
6
Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
Tumor Initiation and Maintenance Program, National Cancer Institute-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
8
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
9
Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
10
Department of Molecular and Cell Biology, University of California, Merced, Merced, CA 95340, USA.
11
Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
12
Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
13
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
14
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
15
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA.
16
Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
17
Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
18
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
19
Department of Biomedical Sciences, University of Padua, Padova, PD 35122, Italy.
20
National Research Council Neuroscience Institute, Padova, PD 35122, Italy.
21
Papé Family Pediatric Research Institute, Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239, USA.
22
Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97239, USA.
23
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.

Abstract

A major limitation of targeted cancer therapy is the rapid emergence of drug resistance, which often arises through mutations at or downstream of the drug target or through intrinsic resistance of subpopulations of tumor cells. Medulloblastoma (MB), the most common pediatric brain tumor, is no exception, and MBs that are driven by sonic hedgehog (SHH) signaling are particularly aggressive and drug-resistant. To find new drug targets and therapeutics for MB that may be less susceptible to common resistance mechanisms, we used a developmental phosphoproteomics approach in murine granule neuron precursors (GNPs), the developmental cell of origin of MB. The protein kinase CK2 emerged as a driver of hundreds of phosphorylation events during the proliferative, MB-like stage of GNP growth, including the phosphorylation of three of the eight proteins commonly amplified in MB. CK2 was critical to the stabilization and activity of the transcription factor GLI2, a late downstream effector in SHH signaling. CK2 inhibitors decreased the viability of primary SHH-type MB patient cells in culture and blocked the growth of murine MB tumors that were resistant to currently available Hh inhibitors, thereby extending the survival of tumor-bearing mice. Because of structural interactions, one CK2 inhibitor (CX-4945) inhibited both wild-type and mutant CK2, indicating that this drug may avoid at least one common mode of acquired resistance. These findings suggest that CK2 inhibitors may be effective for treating patients with MB and show how phosphoproteomics may be used to gain insight into developmental biology and pathology.

PMID:
30206138
DOI:
10.1126/scisignal.aau5147

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