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Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis
Cancer Cell  (IF31.743),  Pub Date : 2021-08-12, DOI: 10.1016/j.ccell.2021.07.006
Kosuke Tanaka, Helena A. Yu, Shaoyuan Yang, Song Han, S. Duygu Selcuklu, Kwanghee Kim, Shriram Ramani, Yogesh Tengarai Ganesan, Allison Moyer, Sonali Sinha, Yuchen Xie, Kota Ishizawa, Hatice U. Osmanbeyoglu, Yang Lyu, Nitin Roper, Udayan Guha, Charles M. Rudin, Mark G. Kris, Emily H. Cheng

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.