Signalling Pathways Associated with Gefitinib Resistance in Glioblastoma
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Abstract
Glioblastoma multiforme (GBM) is the most aggressive brain tumor in adults and
remains incurable despite multimodal intensive treatment regimens. The majority of GBM
tumors show a mutated or overexpressed EGFR. However, the kinase domain mutations that
usually correlate with response to the tyrosine kinase inhibitors in other cancers are infrequent in
glioblastomas and phase II trials of the tyrosine kinase inhibitor (TKI), gefitinib showed no
survival benefit in glioblastoma. Furthermore, tumors treated with the TKIs will inevitably recur
highlighting the need to identify signalling pathways involved in GBM resistance to TKIs. To
this end, we treated GBM cells that overexpress EGFR with increasing concentrations of
Gefitinib and isolated resistant clones. These resistant clones were subject to RNAseq and the
expression of several genes was found to be upregulated in these clones. These genes are all
tyrosine kinase receptors and include ROS1, DDR1 and PDGFRA. The upregulation of these
genes was confirmed at the protein level by western blot. Treatment with ROS1 inhibitors in
ROS1 overexpressing clones led to sensitization of these clones to gefitinib. Our current study
led to the discovery of alternative pathways used by GBM cells to evade cell death following
treatment with gefitinib and identifies new therapeutic targets to prevent GBM cell resistance to
the drug.