Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis

• Published in: Cancer cell 2021-09, Vol.39 (9), p.1245-1261.e6
• Main Authors: Tanaka, Kosuke, Yu, Helena A., Yang, Shaoyuan, Han, Song, Selcuklu, S. Duygu, Kim, Kwanghee, Ramani, Shriram, Ganesan, Yogesh Tengarai, Moyer, Allison, Sinha, Sonali, Xie, Yuchen, Ishizawa, Kota, Osmanbeyoglu, Hatice U., Lyu, Yang, Roper, Nitin, Guha, Udayan, Rudin, Charles M., Kris, Mark G., Hsieh, James J., Cheng, Emily H.
• Format: Article
• Language: English
• Subjects: Acrylamides - pharmacology; Aniline Compounds - pharmacology; apoptosis; Apoptosis Regulatory Proteins - metabolism; Aurora B kinase; Aurora Kinase B - antagonists & inhibitors; BCL-2 family; Bcl-2-Like Protein 11 - metabolism; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Cell Line, Tumor; drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Screening Assays, Antitumor; Drug Synergism; drug tolerance; EMT; epidermal growth factor receptor; Epithelial-Mesenchymal Transition - drug effects; Gene Expression Regulation, Neoplastic - drug effects; High-Throughput Screening Assays; Humans; lineage plasticity; lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; mitotic catastrophe; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins - metabolism; Small Molecule Libraries - pharmacology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2021.07.006

The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by the eventual development of acquired resistance. We hypothesize that enhancing apoptosis through combination therapies can eradicate cancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughput screening of a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibition stabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivity to respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but also overcomes resistance beyond EMT. [Display omitted] •Aurora kinase inhibitors combined with osimertinib prevent and overcome resistance•Concurrent inhibition of EGFR and AURKB maximizes BIM- and PUMA-mediated apoptosis•EMT activates ATR-CHK1-AURKB and sensitizes cancer cells to these kinase inhibitors•Mitotic catastrophe triggered by ATR-CHK1-AURKB inhibitors involves BIM and BAX/BAK Tanaka et al. identify Aurora kinase inhibitors as potent enhancers of osimertinib-induced apoptosis by HTS. Concurrent inhibition of EGFR and AURKB maximizes BIM- and PUMA-mediated apoptosis to eradicate cancer cells. Osimertinib resistance caused by EMT activates ATR-CHK1-AURKB and engenders hypersensitivity to these kinase inhibitors by activating BIM-mediated mitotic catastrophe.