Journal
CANCER CELL
Volume 39, Issue 9, Pages 1245-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2021.07.006
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Funding
- NIH [R01CA125562, R01CA252658]
- Lung Cancer Discovery Award from the American Lung Association
- NCI Cancer Center Support Grant [P30CA008748]
- Japan Society for the Promotion of Science
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Combination therapy with EGFR and Aurora B inhibitors enhances osimertinib-induced apoptosis, effectively eliminating cancer cells and overcoming resistance, mainly by affecting the stability of BIM and PUMA.
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 similar to 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.
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