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Combinations of proteasome inhibitors with obatoclax are effective for small cell lung cancer

Yan-ping Yin1,2,3, Wen-hao Shi4, Ke Deng1,2,3, Xiao-li Liu1,2,3, Hong Li1,3, Xiao-tong Lv1,2,3, Vivian Wai Yan Lui5, Chen Ding6,7,8, Bo Hong1,3, Wen-chu Lin1,3
1 High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China
2 University of Science and Technology of China, Hefei 230036, China
3 Key Laboratory of High Magnetic Field and Ion Beam Physical Biology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China
4 State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Lifeomics, National Center for Protein Sciences (The PHOENIX Center, Beijing), Beijing 102206, China
5 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
6 State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200433, China
7 State Key Laboratory of Cell Differentiation and Regulation, College of Life Science, Henan Normal University, Xinxiang 453007, China
8 Academy of Medical Science, Zhengzhou University, Zhengzhou 450052, China
Correspondence to: Chen Ding: chend@fudan.edu.cn, Bo Hong: bhong@hmfl.ac.cn, Wen-chu Lin: wenchu@hmfl.ac.cn,
DOI: 10.1038/s41401-020-00544-w
Received: 19 May 2020
Accepted: 18 September 2020
Advance online: 2 November 2020

Abstract

Proteasome inhibitors, bortezomib (BTZ), and carfilzomib (CFZ) are approved drugs for hematological malignancies, but lack anticancer activities against most solid tumors. Small cell lung cancer (SCLC) is a very aggressive neuroendocrine carcinoma of the lungs demanding effective therapy. In this study we investigated whether BTZ or CFZ combined with obatoclax (OBX), an antagonist for MCL-1 and a pan-BCL family inhibitor, could cause synergistic growth inhibition of SCLC cells. We showed that combined application of BTZ or CFZ with OBX caused synergistic growth inhibition of human SCLC cell lines (H82, H526, DMS79, H196, H1963, and H69) than single agent alone. Both BTZ–OBX and CFZ–OBX combinations displayed marked synergism on inducing apoptosis (~50% increase vs BTZ or CFZ alone). A comprehensive proteomics analysis revealed that BTZ preferentially induced the expression of MCL-1, an antiapoptotic protein, in SCLC cells. Thus, proteasome inhibitor–OBX combinations could specifically induce massive growth inhibition and apoptosis in SCLC cells. Subsequent proteome-wide profiling analysis of activated transcription factors suggested that BTZ- or CFZ-induced MCL-1 upregulation was transcriptionally driven by FOXM1. In nude mice bearing in SCLC H82 xenografts, both BTZ–OBX, and CFZ–OBX combinations exhibited remarkable antitumor activities against SCLC tumors evidenced by significant reduction of tumor size and the proliferation marker Ki-67 signals in tumor tissues as compared with single agent alone. Thus, proteasome inhibitor–OBX combinations are worth immediate assessments for SCLC in clinical settings.
Keywords: small cell lung cancer; obatoclax; bortezomib; carfilzomib; MCL-1; apoptosis; FOXM1; proteomics analysis

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