Abstract
Glioblastoma (GBM) patients have extremely poor prognoses, and currently no effective treatment available including surgery, radiation, and chemotherapy. MAPK-interacting kinases (MNK1/2) as the downstream of the MAPK-signaling pathway regulate protein synthesis in normal and tumor cells. Research has shown that targeting MNKs may be an effective strategy to treat GBM. In this study we investigated the antitumor activity of osimertinib, an FDA-approved epidermal growth factor receptor (EGFR) inhibitor, against patient-derived primary GBM cells. Using high-throughput screening approach, we screened the entire panel of FDA-approved drugs against primary cancer cells derived from glioblastoma patients, found that osimertinib (3 μM) suppressed the proliferation of a subset (10/22) of EGFR-negative GBM cells (>50% growth inhibition). We detected the gene expression difference between osimertinib-sensitive and -resistant cells, found that osimertinib-sensitive GBM cells displayed activated MAPK-signaling pathway. We further showed that osimertinib potently inhibited the MNK kinase activities with IC50 values of 324 nM and 48.6 nM, respectively, against MNK1 and MNK2 kinases; osimertinib (0.3–3 μM) dose-dependently suppressed the phosphorylation of eukaryotic translation initiation factor 4E (eIF4E). In GBM patient-derived xenografts mice, oral administration of osimertinib (40 mg· kg−1 ·d−1, for 18 days) significantly suppressed the tumor growth (TGI = 74.5%) and inhibited eIF4E phosphorylation in tumor cells. Given the fact that osimertinib could cross the blood–brain barrier and its toxicity was well tolerated in patients, our results suggest that osimertinib could be a new and effective drug candidate for the EGFR-negative GBM patients.
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Acknowledgements
This study was supported by the National Natural Science Foundation of China (grants 81773777, 81673469, 81703559, and 81172407), the Natural Science Foundation of Anhui Province (grants 1808085MH274 and 1908085MH259), the China Post-doctoral Science Foundation (grants 2018T110634, 2018M630720, and 2019M652057), the Post-doctoral Science Foundation of Anhui Province (grant 2018B279), Science and Technology Project grants from Anhui Province (grants 1508085QHl84, 1606c08235, and 1604a0802069), the Fundamental Research Fund for Central Universities (WK 9110000032), the Frontier Science Key Research Program of the Chinese Academy of Sciences (grant QYZDB-SSW-SLH037), the CASHIPS Director’s Fund (grant BJPY2019A03), the Key Program of the 13th Five-Year Plan of CASHIPS (grant KP-2017-26), and the Presidential Foundation of CASHIPS (grant YZJJ2018QN17). A portion of this work was supported by the High Magnetic Field Laboratory of Anhui Province.
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QSL, CSN, and WCW designed the project and wrote the manuscript. CC, CDC, HW, LW, ZWW, and ZRJ performed the experiments and collected the data. CC, HW, ALW, and CH drafted the manuscript. YFD, WXN, and SQ analyzed the data. ZPQ and JL revised the manuscript. All the authors read and approved the final manuscript.
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Chen, C., Cheng, Cd., Wu, H. et al. Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway. Acta Pharmacol Sin 42, 108–114 (2021). https://doi.org/10.1038/s41401-020-0418-2
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DOI: https://doi.org/10.1038/s41401-020-0418-2
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