Receptor tyrosine kinase AXL is correlated with poor prognosis and induces temozolomide resistance in glioblastoma

AIMS: To investigate the functions and underlying mechanisms of AXL receptor tyrosine kinase (AXL) in tumor proliferation and chemoresistance to temozolomide (TMZ) in glioblastoma (GBM). METHODS: With a kinome-wide bioinformatics analysis, AXL was found to be an essential kinase candidate in TMZ chemoresistance promotion. Additionally, the biological functions of AXL in oncogenesis and TMZ resistance were clarified by using qRT-PCR, Western blotting, and in vivo intracranial GBM xenograft models followed the induction of TMZ resistance in U87 or U251 cells. Additionally, immunohistochemistry (IHC) assays were used to investigate the correlation of AXL on the survival of patients with glioma. Finally, the Chou-Talalay model was performed to confirm the synergistic effect of AXL inhibitor TP-0903 with TMZ. RESULTS: Elevated AXL expression significantly correlated with adverse outcomes of patients with glioma, especially patients with GBM. Moreover, AXL knockdown reduced tumorigenesis and TMZ resistance in vitro and in vivo; however, exogenous AXL overexpression induced TMZ resistance in GBM. Lastly, a specific AXL inhibitor, TP-0903, dramatically decreased tumor growth and increased sensitivity to TMZ via a synergistic effect. CONCLUSION: AXL contributed to chemoresistance to TMZ in GBM and could be used as a novel prognostic biomarker and therapeutic target for GBM.