Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis Journal Article
| Authors: | Tanaka, K.; Yu, H. A.; Yang, S.; Han, S.; Selcuklu, S. D.; Kim, K.; Ramani, S.; Ganesan, Y. T.; Moyer, A.; Sinha, S.; Xie, Y.; Ishizawa, K.; Osmanbeyoglu, H. U.; Lyu, Y.; Roper, N.; Guha, U.; Rudin, C. M.; Kris, M. G.; Hsieh, J. J.; Cheng, E. H. |
| Article Title: | Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis |
| 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. © 2021 Elsevier Inc. |
| Keywords: | apoptosis; epidermal growth factor receptor; lung cancer; drug resistance; drug tolerance; aurora b kinase; emt; bcl-2 family; mitotic catastrophe; lineage plasticity |
| Journal Title: | Cancer Cell |
| Volume: | 39 |
| Issue: | 9 |
| ISSN: | 1535-6108 |
| Publisher: | Cell Press |
| Date Published: | 2021-09-13 |
| Start Page: | 1245 |
| End Page: | 1261.e6 |
| Language: | English |
| DOI: | 10.1016/j.ccell.2021.07.006 |
| PUBMED: | 34388376 |
| PROVIDER: | scopus |
| PMCID: | PMC8440494 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 October 2021 -- Source: Scopus |
