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Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway

Authors: Cheng Chen1,2, Chuan-dong Cheng1,2,3,4, Hong Wu1,5, Zuo-wei Wang1,2, Li Wang1, Zong-ru Jiang1,5, Ao-li Wang1,5, Chen Hu1,5, Yong-fei Dong3,4, Wan-xiang Niu3,4, Shuang Qi1,5, Zi-ping Qi1,5, Jing Liu1,5, Wen-chao Wang1,5, Chao-shi Niu3,4, Qing-song Liu1,2,5,6,7
1 High Magnetic Field Laboratory, Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
2 University of Science and Technology of China, Hefei 230036, China
3 Department of Neurosurgery, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230036, China
4 Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei 230031, China
5 Precision Medicine Research Laboratory of Anhui Province, Hefei 230088, China
6 Precision Targeted Therapy Discovery Center, Institute of Technology Innovation, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230088, China
7 Institutes of Physical Science and Information Technology, Anhui University, Hefei 230601, China
Correspondence to: Wen-chao Wang: wwcbox@hmfl.ac.cn, Chao-shi Niu: niuchaoshi@ustc.edu.cn, Qing-song Liu: qsliu97@hmfl.ac.cn,
DOI: 10.1038/s41401-020-0418-2
Received: 6 January 2020
Accepted: 12 April 2020
Advance online: 12 May 2020

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.
Keywords: glioblastoma; osimertinib; temozolamide; MAPK-signaling pathway; MNK; eukaryotic translation initiation factor 4E

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