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Preclinical evaluation of a new ROS1 inhibitor to overcome resistance to EGFR therapy in glioblastoma
Author(s) -
Aljohani Hashim M.,
Bahassi El Mustapha
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.674.27
Subject(s) - crizotinib , ros1 , gefitinib , cancer research , erlotinib , epidermal growth factor receptor , medicine , lung cancer , targeted therapy , cancer , tyrosine kinase , oncogene , receptor tyrosine kinase , cabozantinib , cell cycle , oncology , adenocarcinoma , receptor , malignant pleural effusion
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 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 diminished Crizotinib binding, due to ROS1 mutations in Crizotinib binding pocket. Interestingly, our initial analysis suggests that our lead compound ROS1‐Ic might not be affected by these mutations, highlighting the potential therapeutic value of this compound. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .