Signalling Pathways Associated with Gefitinib Resistance in Glioblastoma

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HASHIM MUSALLAM HAMOUD ALJOHANI
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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.
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