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.
| Original language | English (US) |
|---|---|
| Article number | eaau5147 |
| Journal | Science Signaling |
| Volume | 11 |
| Issue number | 547 |
| DOIs | |
| State | Published - Sep 11 2018 |
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ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology
Cite this
Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma. / Purzner, Teresa; Purzner, James; Buckstaff, Taylor; Cozza, Giorgio; Gholamin, Sharareh; Rusert, Jessica M.; Hartl, Tom A.; Sanders, John; Conley, Nicholas; Ge, Xuecai; Langan, Marc; Ramaswamy, Vijay; Ellis, Lauren; Litzenburger, Ulrike; Bolin, Sara; Theruvath, Johanna; Nitta, Ryan; Qi, Lin; Li, Xiao Nan; Li, Gordon; Taylor, Michael D.; Wechsler-Reya, Robert J.; Pinna, Lorenzo A.; Cho, Yoon-Jae; Fuller, Margaret T.; Elias, Joshua E.; Scott, Matthew P.
In: Science Signaling, Vol. 11, No. 547, eaau5147, 11.09.2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Developmental phosphoproteomics identifies the kinase CK2 as a driver of Hedgehog signaling and a therapeutic target in medulloblastoma
AU - Purzner, Teresa
AU - Purzner, James
AU - Buckstaff, Taylor
AU - Cozza, Giorgio
AU - Gholamin, Sharareh
AU - Rusert, Jessica M.
AU - Hartl, Tom A.
AU - Sanders, John
AU - Conley, Nicholas
AU - Ge, Xuecai
AU - Langan, Marc
AU - Ramaswamy, Vijay
AU - Ellis, Lauren
AU - Litzenburger, Ulrike
AU - Bolin, Sara
AU - Theruvath, Johanna
AU - Nitta, Ryan
AU - Qi, Lin
AU - Li, Xiao Nan
AU - Li, Gordon
AU - Taylor, Michael D.
AU - Wechsler-Reya, Robert J.
AU - Pinna, Lorenzo A.
AU - Cho, Yoon-Jae
AU - Fuller, Margaret T.
AU - Elias, Joshua E.
AU - Scott, Matthew P.
PY - 2018/9/11
Y1 - 2018/9/11
N2 - 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.
AB - 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.
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U2 - 10.1126/scisignal.aau5147
DO - 10.1126/scisignal.aau5147
M3 - Article
VL - 11
JO - Science Signaling
JF - Science Signaling
SN - 1937-9145
IS - 547
M1 - eaau5147
ER -