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AXL as a modulator of sunitinib response in glioblastoma cell lines
Olga Martinho1, Luis Eduardo Zucca2, Rui Manuel Reis1
1Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal; Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
Abstract:
Receptor tyrosine kinase (RTK) targeted therapy has been explored for glioblastoma treatment. However, it is unclear which RTK inhibitors are the most effective and there are no predictive biomarkers available. We recently identified the RTK AXL as a putative target for the pan-RTK inhibitors cediranib and sunitinib, which are under clinical trials for glioblastoma patients. Here, we provide evidence that AXL activity can modulate sunitinib response in glioblastoma cell lines. We found that AXL knockdown conferred lower sensitivity to sunitinib by rescuing migratory defects and inhibiting apoptosis in cells expressing high AXL basal levels. Accordingly, overactivation of AXL by its ligand GAS6 rendered AXL positive glioblastoma cells more sensitive to sunitinib. AXL knockdown induced a cellular rewiring of several growth signaling pathways through activation of RTKs, such as EGFR, as well as intracellular pathways such as MAPK and AKT. The combination of sunitinib with a specific AKT inhibitor reverted the resistance of AXL-silenced cells to sunitinib. Together, our results suggest that sunitinib inhibits AXL and AXL activation status modulates therapy response of glioblastoma cells to sunitinib. Moreover, it indicates that combining sunitinib therapy with AKT pathway inhibitors could overcome sunitinib resistance.
Insights
AXL receptor activity influences glioblastoma cell response to sunitinib therapy. Combining sunitinib with AKT inhibitors may overcome treatment resistance in patients with glioblastoma.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Receptor tyrosine kinase (RTK) targeted therapies are investigated for glioblastoma (GBM).
- Effectiveness of RTK inhibitors and predictive biomarkers for GBM remain unclear.
- AXL receptor tyrosine kinase is a potential target for pan-RTK inhibitors like sunitinib.
Purpose of the Study:
- To investigate the role of AXL receptor activity in modulating glioblastoma cell response to sunitinib.
- To explore AXL as a predictive biomarker for sunitinib efficacy in glioblastoma.
- To identify potential combination therapies to overcome sunitinib resistance.
Main Methods:
- Glioblastoma cell lines with varying AXL expression levels were utilized.
- AXL knockdown and AXL overactivation (via GAS6) were experimentally induced.
- Cellular migration, apoptosis, and signaling pathway activation (EGFR, MAPK, AKT) were assessed.
- Response to sunitinib and combination therapy with an AKT inhibitor was evaluated.
Main Results:
- AXL knockdown reduced sunitinib sensitivity by rescuing migration and inhibiting apoptosis in high-AXL cells.
- AXL overactivation increased sunitinib sensitivity in AXL-positive glioblastoma cells.
- AXL knockdown led to pathway rewiring, activating EGFR, MAPK, and AKT.
- Combination of sunitinib with an AKT inhibitor reversed sunitinib resistance in AXL-silenced cells.
Conclusions:
- Sunitinib's mechanism involves AXL inhibition, and AXL activation status impacts glioblastoma therapy response.
- AXL activity serves as a potential biomarker for sunitinib treatment efficacy.
- Combining sunitinib with AKT pathway inhibitors may represent a viable strategy to overcome treatment resistance in glioblastoma.
