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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.

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

Cancer cell (2021-08-14)
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, James J Hsieh, Emily H Cheng
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Millipore
Emetine, Dihydrochloride, Principal alkaloid of ipecac, isolated from the ground roots of Uragoga ipecacuanha.
Sigma-Aldrich
Anti-phospho-Histone H3 (Ser10) Antibody, Mitosis Marker, Upstate®, from rabbit
Sigma-Aldrich
Monoclonal Anti-α-Tubulin antibody produced in mouse, clone DM1A, ascites fluid
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Anti-FOXO3a/FKHRL1 Antibody, Upstate®, from rabbit