Aljohani, Hashim Koncar, Robert F. Zarzour, Ahmad Park, Byung Sun Lee, So Ha Bahassi, El Mustapha 2024-01-20T06:31:08Z 2024-01-20T06:31:08Z 2021-09-05 2015-08-21 1949-2553 https://pubs.kist.re.kr/handle/201004/125114 Glioblastoma (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, tumors treated with tyrosine kinase inhibitors (TKIs) will inevitably recur highlighting the need to identify signalling pathways involved in GBM resistance to these drugs. 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. These genes are mainly tyrosine kinase receptors and include ROS1, DDR1 and PDGFRA and are known to control several downstream targets of EGFR. The upregulation of ROS1 and DDR1 was confirmed at the protein level by western blot. Treatment with a potent and highly specific pyrazole ROS1 inhibitor in ROS1 overexpressing clones led to a sensitization of these cells to low concentrations of gefitinib. Combined treatment with gefitinib and ROS1 inhibitor induces massive cell death by apoptosis following a prolonged S phase cell cycle arrest. 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. English IMPACT JOURNALS LLC GROWTH-FACTOR RECEPTOR CANCER INVASION INHIBITION IDENTIFICATION ASSOCIATION THERAPY GLIOMAS FUSION POTENT ROS1 amplification mediates resistance to gefitinib in glioblastoma cells Article 10.18632/oncotarget.3981 1 ONCOTARGET, v.6, no.24, pp.20388 - 20395 ONCOTARGET 6 24 20388 20395 scie scopus 000360138200058 2-s2.0-84940191343 Oncology Cell Biology Oncology Cell Biology Article GROWTH-FACTOR RECEPTOR CANCER INVASION INHIBITION IDENTIFICATION ASSOCIATION THERAPY GLIOMAS FUSION POTENT tyrosine kinase inhibitors EGFR gefitinib ROS1 DDR1