Effective Inhibition of MYC-Amplified Group 3 Medulloblastoma Through Targeting EIF4A1

Yang Zhao,1,* Tiantian Li,2,* Shuaiwei Tian,1,* Wei Meng,1 Yi Sui,2 Jian Yang,1 Baocheng Wang,1 Zhuangzhuang Liang,1 Heng Zhao,1 Yipeng Han,1 Yujie Tang,1,2 Lei Zhang,2 Jie Ma1 1Department of Pediatric Neurosurgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Key Laboratory of Cell Differentiation and Apoptosis of the National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jie MaDepartment of Pediatric Neurosurgery, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Yangpu District, Shanghai 200092, People’s Republic of ChinaTel +86- 13818138498Fax +86-21- 65795173Email majie@xinhuamed.com.cnLei ZhangKey Laboratory of Cell Differentiation and Apoptosis of the National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, 280 South Chongqing Road, Huangpu, Shanghai 200025, People’s Republic of ChinaTel +86-13918539872Fax +86-21-6415 4900Email lei.zhang2012@sjtu.edu.cnPurpose: In medulloblastoma (MB), group 3 (G3) patients with MYC amplification tend to exhibit worse prognosis, thus creating a need for novel effective therapies. As the driver and crucial dependency for MYC-amplified G3-MB, MYC has been proven to be a prospective therapeutic target. Here, we aimed to identify novel effective therapeutic strategies against MYC-amplified G3-MB via targeting MYC translation.Materials and Methods: Major components of translation initiation complex eIF4F were subjected to MB tumor dataset analysis, and EIF4A1 was identified to be a potential therapeutic target of MYC-amplified G3-MB. Validation was performed through genetic or pharmacological approaches with multiple patient-derived tumor models of MYC-amplified G3-MB in vitro and in vivo. Underlying mechanisms were further explored by Western blot, quantitative real-time PCR and mass spectrometry (MS) analyses.Results: MB tumor datasets analyses showed that EIF4A1 was significantly up-regulated in G3-MB patients relative to normal cerebella, positively correlated with MYC in G3-MB at transcriptional level and a crucial cancer dependency in MYC-amplified G3-MB cells. Targeting EIF4A1 with a CRISPR/Cas9 approach or small-molecule inhibitor silvestrol effectively attenuated growth in multiple preclinical models of MYC-amplified G3-MB via blocking proliferation and inducing apoptosis. Mechanistically, EIF4A1 inhibition effectively impeded MYC expression at translational level, and its potency was positively associated with MYC level. Whole-proteome MS analysis of silvestrol-treated cells further unveiled other biological functions and pathways influenced by EIF4A1 inhibition.Conclusion: Our investigation shows that interrupting MYC translation by EIF4A1 inhibition could be a potential effective therapeutic approach when treating patients with MYC-amplified G3-MB.Keywords: eIF4F complex, EIF4A1, MYC-amplified group 3 medulloblastoma, Silvestrol, translation inhibition