Cancer stem cells promote neoplastic growth, in part by deregulating asymmetric cell division and enhancing self-renewal. To uncover mechanisms and potential therapeutic targets in glioma stem cell (GSC) self-renewal, we performed a genetic suppressor screen for kinases to reverse the tumor phenotype of our Drosophila brain tumor model and identified dCdk5 as a critical regulator. CDK5, the human ortholog of dCdk5 (79% identity), is aberrantly activated in GBMs and tightly aligned with both chromosome 7 gains and stem cell markers affecting tumor-propagation. Our investigation revealed that pharmaceutical inhibition of CDK5 prevents GSC self-renewal in vitro and in xenografted tumors, at least partially by suppressing CREB1 activation independently of PKA/cAMP. Finally, our TCGA GBM data analysis revealed that CDK5, stem cell, and asymmetric cell division markers segregate within non-mesenchymal patient clusters, which may indicate preferential dependence on CDK5 signaling and sensitivity to its inhibition in this group.
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This work was also supported by US Public Health Service NIH (R01 CA176659 and CA149107 to D.J.B. and K25CA181503 to J.K.), the Winship Cancer Institute NCI Cancer Center (P30CA138292), and the Georgia Research Alliance (to D.J.B.).
Supplemental Information includes Supplemental Experimental Procedures, six figures, and two tables and can be found with this article online at https://doi.org/10.1016/j.celrep.2018.04.016.
Mukherjee, Subhas; Tucker-Burden, Carol; Kaissi, Emily; Newsam, Austin; Duggireddy, Hithardhi; Chau, Monica; Zhang, Changming; Diwedi, Bhakti; Rupji, Manali; Seby, Sandra; Kowalski, Jeanne; Kong, Jun; Read, Renee; and Brat, Daniel J., "CDK5 Inhibition Resolves PKA/cAMP-Independent Activation of CREB1 Signaling in Glioma Stem Cells" (2018). Neurology Faculty Publications. 24.