Abstract C160: An RNAi kinome screen identifies YES1 as a potential target for glioblastoma

Glioblastoma stem like cells (GSC) are known to have gene expression patterns and growth phenotypes more similar to the tumor of origin than do traditional glioma cell lines grown in serum. They also exhibit increased resistance to drugs and radiation and are likely to be responsible for tumor recurrence following therapy. As a result, it is important to identify therapeutic targets for these cells. Toward this end, we have conducted RNAi kinome screens in GSCs to identify genes that are required for their growth and survival. In addition, glioblastomas (GBM) often have significant regions of hypoxia and GSCs tend to be resistant to hypoxia. We have therefore conducted shRNA screens in both normoxic and hypoxic conditions and screened three independent patient derived GSC lines. Of 501 kinases screened, 8-11% were scored as hits with at least 2 shRNAs per kinase in each cell line, but only ∼2% were common hits for all the cell lines in both oxygen conditions. The majority of the hits were shared in both oxygen conditions, but about one sixth were specific to hypoxia in each of the cell lines. However, none of the hypoxia specific hits were common to all three cell lines. Several genes well known to have a role in GBM such as EGFR, CDK4 and KDR were scored as common hits. The non-receptor associated tyrosine kinase YES1 was scored as a novel hit common to all the three cell lines in both the oxygen conditions. YES1 is overexpressed in GBM and several other solid tumors. Depletion of YES1 expression by shRNA and CRISPR was found to be strongly growth inhibitory in GSCs suggesting that it could be a therapeutic target for GBM. Ongoing experiments include studying the mechanism of YES1 associated cell death. Citation Format: Surbhi Goel- Bhattacharya, Sejuti Sengupta, Brent H. Cochran. An RNAi kinome screen identifies YES1 as a potential target for glioblastoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C160.