A kinome-wide RNAi screen in Drosophila glia reveals new kinases that mediate cell proliferation and survival in human glioblastoma. Renee Read^1,2, Tim Fenton³, German Gomez³, Jill Wykosky³, Scott Vandenberg⁴, Ivan Babic³, Akio Iwanami⁵, Huijun Yang³, Webster Cavenee³, Paul Mischel³, Frank Furnari³, John Thomas². 1) Department of Pharmacology, Emory University School of Medicine, Atlanta, GA; 2) The Salk Institute for Biological Studies, Molecular Neurobiology Laboratory, La Jolla, CA; 3) Ludwig Institute for Cancer Research, University of California - San Diego, La Jolla, CA; 4) Department of Pathology, University of California - San Diego, La Jolla, CA; 5) Department of Orthopaedic Surgery, Keio University School of Medicine, Tokyo, Japan.

   Glioblastoma (GBM), the most common primary malignant brain tumor, is incurable with current therapies. Genetic and molecular analyses show that GBMs frequently display mutations that activate receptor tyrosine kinase (RTK) and Pi-3 kinase (PI3K) signaling pathways. In Drosophila melanogaster, activation of RTK and PI3K pathways in glial progenitor cells creates malignant neoplastic tumors that display many features of human GBM. We used this Drosophila GBM model to perform a kinome-wide genetic screen for genes required for RTK-PI3K dependent neoplastic transformation. Human orthologs of novel kinases uncovered by these screens were functionally assessed in mammalian GBM models and human tumors. Our results revealed that a small number of these human kinases are subject to alterations in tumor cells. In particular, the atypical RIOK1 and RIOK2 kinases become overexpressed in GBM cells in response to Akt activity downstream of RTK and PI3K signaling. When overexpressed, RIOK2 upregulated Akt signaling and promoted tumorigenesis. Conversely, reduced expression of RIOK1 or RIOK2 disrupted Akt signaling and caused cell cycle exit, apoptosis, and chemosensitivity. These results imply that, in GBM cells, the RIO kinases create a feedforward loop that promotes and maintains oncogenic Akt activity. Further study of the RIO kinases as well as other kinases identified in our Drosophila screen may reveal new insights into signaling defects underlying GBM and related cancers.