Abstract A02: A kinome-wide RNAi screen in Drosophila glia and human GBM models reveals Stk17A drives neoplastic glial proliferation and migration

Abstract

Abstract Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, are highly proliferative, diffusely invasive, and incurable by current therapies. Genetic and molecular analyses reveal that GBMs frequently harbor activating mutations in the EGFR receptor tyrosine kinase (EGFR) and Pi-3 kinase (PI3K) signaling pathways. While the ability of these mutations to drive gliomagenesis has been verified in mouse models, current data also indicate that EGFR and PI3K signaling cooperates with as yet unknown factors to drive its invasive pathology and therapeutic resistance in GBM. To identify such factors, we performed a cross-species, multidisciplinary genetic screen in both Drosophila melanogaster and mammalian GBM model systems designed to identify novel genes that augment EGFR- and PI3K- dependent neoplasia. Our results in both Drosophila and GBM cell culture and animal model systems indicate that Stk17A, a cytoplasmic serine-threonine kinase subject to copy-gain and overexpression in GBM, is necessary for GBM cell proliferation and invasion. Our data also illustrate that overexpression of Stk17A in combination with oncogenic EGFR mutations is sufficient to promote increased glial cell proliferation and invasion. Furthermore, in our GBM model systems, we find that Stk17A overexpression stimulates increased phosphorylation and activity of non-muscle myosin II regulatory light chain (MRLC), a known Stk17A substrate and key regulator of the cell cycle and cellular motility, which itself is required for neoplastic glial transformation. Finally, oncogenomic analysis of GBMs and other high-grade gliomas reveal that Stk17A becomes overexpressed in association with EGFR-PI3K mutations, and Stk17A copy-gain and overexpression are significantly associated with poor prognosis in patients. Together, these mechanistic insights indicate that Stk17A potentiates the oncogenenic effects of EGFR- and PI3K-driven tumors through the upregulation of MLRC activity, and suggest that Stk17A may serve as a novel therapeutic target for EGFR-PI3K dependent GBMs and high-grade gliomas. Current work is continuing to examine the molecular function of Stk17A in the context of GBM, normal glia, and neural stem cells in order to further our understanding of how Stk17A contributes to tumor pathology. Citation Format: Joanna Wardwell-Ozgo, Colleen Mosley, Harley Kornblum, Renee Read. A kinome-wide RNAi screen in Drosophila glia and human GBM models reveals Stk17A drives neoplastic glial proliferation and migration. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A02.