Abstract
Abstract
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 epidermal growth factor receptor (EGFR); however, tumors treated with EGFR inhibitors such as gefitinib or erlotinib inevitably recur. This recurrence highlights the need to identify signaling pathways involved in GBM resistance to EGFR therapy that may serve as targets for intervention. In our recently published work, we found that activation of the ROS1 pathway is a primary mechanism by which glioma cells become resistant to EGFR-targeted therapy. ROS1 is a proto-oncogene receptor tyrosine kinase activated by chromosomal rearrangement in several human cancers, including non-small cell lung cancer (NSCLC), cholangiocarcinoma, gastric cancer, ovarian cancer, and glioblastoma. We therefore designed, synthesized, and screened a series of new ROS1 inhibitors. The lead compound, ROS-Ic, is very potent (IC50 = 24nM) and highly specific to ROS1 protein. Treatment of gefitinib-resistant GBM cells with ROS1-lc sensitized the resistant cells to low concentrations of gefitinib, resulting in apoptosis following a prolonged S-phase cell cycle arrest. When compared to crizotinib, an FDA-approved small-molecule tyrosine kinase inhibitor currently used to treat ALK- and ROS1+ NSCLC patients, ROS-Ic showed superior cytotoxic activity in vitro towards ROS1-positive GBM cells. Crizotinib resistance is thought to be due to abolished crizotinib binding by ROS1 mutations in crizotinib binding pocket. Interestingly, the binding of our leading compound ROS1-Ic was not affected by these mutations and crizotinib-resistant cells harboring these mutations were still sensitive to ROS1-Ic, highlighting the potential therapeutic value of this compound.
Citation Format: Hashim M. Aljohani, Mohamed Aittaleb, Byung Sun Park, So Ha Lee, El Mustapha Bahassi. Preclinical evaluation of a new ROS1 inhibitor to overcome resistance to EGFR therapy in glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A141.