Kinome-wide shRNA Screen Identifies the Receptor Tyrosine Kinase {AXL} as a Key Regulator for Mesenchymal Glioblastoma Stem-like Cells

摘要

Summary Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive {MES} GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin {RNA} screening of {MES} and {PN} GSCs. In comparison to {PN} GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase {AXL} in {MES} GSCs. Knockdown of {AXL} significantly decreased {MES} {GSC} self-renewal capacity in?vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of {AXL} with shRNA or pharmacologic inhibitors also increased cell death significantly more in {MES} GSCs. Clinically, {AXL} expression was elevated in the {MES} {GBM} subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified {AXL} as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers.