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

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.

Casein kinase 2 inhibition sensitizes medulloblastoma to temozolomide

“…CX-4945 is currently undergoing multiple phase I/II clinical trials for patients with advanced solid tumors and it is generally well tolerated with low toxicity [32,33]. Our findings are consistent with our recent report that showed CX-4945 treatment could increase survival in Ptch +/− mouse that develop MB like tumors [17]. Altogether, our findings indicate that CX-4945 can be an effective and safer treatment for MB patients.…”

“…In this study, we verified the importance of CK2 in MB tumorigenesis and discovered a novel connection between CK2 and MGMT expression that can lead to new exciting [17]. Since single treatment arms rarely work in the clinic, we expanded on this initial finding and conducted a high-throughput assay to identify FDA-approved drugs that work with CX-4945.…”

Medulloblastoma in the age of molecular subgroups: a review

“…A proposed target downstream of SMO in the SHH pathway is CK2 inhibition, and a phase 1/2 trial using the CK2 inhibitor CX-4945 in recurrent SHH medulloblastoma is currently recruiting patients (NCT03904862). 49…”

“…Proposed targeted therapies in specific molecular subgroups of medulloblastoma, based on data from the following references. 4,10,19,27,29,33,45,49,55,65,73 Inhibition of SMO or CK2 in the SHH subgroup (A), targeting MYC-driven group 3 medulloblastoma using combination therapy with HDAC inhibitors and PI3K pathway inhibition (B) or BET-bromodomain inhibition to downregulate MYC expression (C), LSD1 inhibition in group 3 and group 4 medulloblastoma with GFI1/GFI1B overexpression (D), and CDK4/6 inhibition in non-WNT medulloblastoma (E). Copyright Azuravesta Design.…”

The Eya1 phosphatase mediates Shh-driven symmetric cell division of cerebellar granule cell precursors

“…Changes in phosphorylation state are critical for most growth factor signaling pathways, including Shh signaling (Hillman et al, 2011;Nybakken et al, 2005;Purzner et al, 2018). Thus kinases including Protein kinase A (PKA), aPKC, as well as other phosphatases such as protein phosphatase 2A (PP2A) and Eya1 function as critical regulators of Shh signaling (Atwood et al, 2013;Eisner et al, 2015;Jia et al, 2009;Wang et al, 1999).…”