Kinome-wide shRNA screen identifies the receptor tyrosine kinase AXL as a key regulator for mesenchymal glioblastoma stem-like cells

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.
Highlights • shRNA screen identified kinases that alter GSC viability in a subtype-dependent manner • AXL is highly expressed in mesenchymal GSCs • Targeting AXL decreases mesenchymal GSC self-renewal, viability, and tumorigenicity • AXL expression predicts poor prognosis in several tumor types
To identify mechanistic differences between the mesenchymal and proneural glioblastoma subtypes, Goidts, Nakano, and colleagues performed a phenotypic screen, silencing the whole kinome in patient-derived mesenchymal and proneural glioblastoma stem-like cells (GSCs). AXL was identified as an important regulator of mesenchymal GSC viability and tumorigenicity, making it an attractive therapeutic target.