Glioblastoma multiforme (GBM), the most common primary malignant brain tumor, is 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 Phosphoinositide 3-kinase (PI3K) signaling pathways. While the ability of these mutations to drive gliomagenesis has been verified in mouse models, current data also reveal that EGFR and PI3K signaling cooperates with as yet unknown factors to drive tumor pathology in GBM. To uncover novel genes that augment EGFR- and PI3K- dependent neoplasia, we leveraged use of our novel in vivo Drosophila glioma model and performed a cross-species, multidisciplinary genetic modifier screen in both Drosophila melanogaster and mammalian GBM model systems that identified multiple suppressors of neoplastic growth including, drak, a cytoplasmic serine-threonine kinase.
Our preliminary results in both Drosophila and mammalian GBM model systems indicate that drak and its human ortholog, Stk17A, is necessary for GBM cell proliferation. Our data also illustrate that overexpression of drak in combination with oncogenic EGFR mutations is sufficient to promote increased glial cell proliferation. Furthermore, in our in vivo Drosophila model, we find that drak overexpression stimulates increased phosphorylation and activity of spaghetti squash (sqh), non-muscle myosin II regulatory light chain, a known drak 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 gliomas reveal that Stk17A becomes overexpressed in association with EGFR mutations, and Stk17A copy-gain and overexpression are significantly associated with poor prognosis in patients.
Together, our data suggest that drak potentiates the oncogenenic effects of EGFR through the upregulation of sqh activity and suggests that Stk17A may serve as a novel therapeutic target for EGFR-PI3K dependent GBMs and high-grade gliomas. Current work is aimed at furthering our understanding of drak/Stk17A’s contribution to tumor pathology. We are specifically exploring the molecular function of drak/Stk17A and the signaling pathways in which drak/Stk17A enacts oncogenic transformation.