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

• DOI: 10.1016/j.ccell.2021.07.006
• Publication Date: 2021-08-12T14:27:27Z
• Authors: Kosuke Tanaka; Helena A. Yu; Shaoyuan Yang; Song Han; S. Duygu Selcuklu; Kwanghee Kim; Shriram Ramani; Yogesh Tengarai G...; Allison Moyer; Sonali Sinha; Yuchen Xie; Kota Ishizawa; Hatice U. Osmanbe...; Yang Lyu; Nitin Roper; Udayan Guha; Charles M. Rudin; Mark G. Kris; James J. Hsieh; Emily H. Cheng
• Keywords: Puma; Aurora inhibitor; Mitotic catastrophe; Aurora kinase; Osimertinib; Aurora A kinase

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.