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Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer
Open accessAbstract
Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.
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“An independent study by Shah et al. found that activation of aurora kinase A (AURKA) in TKI-treated drug-tolerant EGFR-mutant cells suppressed drug-induced apoptosis by increasing BIM phosphorylation and subsequent degradation [94].”
From Emerging Insights into Targeted Therapy-Tolerant Persister Cells in Cancer (2021) · cites this paper as [94]
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Metadata
- Authors
- Shah, K. N., Bhatt, R., Rotow, J., Rohrberg, J., Olivas, V., Wang, V. E., Hemmati, G., Martins, M. M., Maynard, A., Kuhn, J., Galeas, J., Donnella, H. J., Kaushik, S., Ku, A., Dumont, S., Krings, G., Haringsma, H. J., Robillard, L., Simmons, A. D., Harding, T. C., McCormick, F., Goga, A., Blakely, C. M., Bivona, T. G., & Bandyopadhyay, S.
- Affiliations
- University of California, San Francisco (US)
- Clovis Oncology (United States) (US)
- Corresponding author
- Bandyopadhyay, Sourav
- ORCID
- Venue
- Nature Medicine
- Published
- 2018-11-26
- Volume
- 25
- Issue
- 1
- Pages
- 111-118
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6324945
- OpenAlex
- W2901591386
- Cited by
- 286
- References
- 43
- Citations by year
- 2026: 19 · 2025: 43 · 2024: 33 · 2023: 37 · 2022: 44 · 2021: 54 · 2020: 37 · 2019: 18 · 2018: 1
- FWCI
- 20.70
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Doris Duke Charitable Foundation (2018110)
- National Cancer Institute (R01CA169338, U01CA217882, U01CA168370, U54CA224081)
- National Institute of General Medical Sciences (R01GM107671)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- AURKA, TPX2, EGFR inhibitors, acquired drug resistance, EGFR-mutant lung adenocarcinoma, drug tolerance, residual disease, apoptosis, synthetic lethality, Aurora kinase inhibitors
- MeSH terms
- Animals, Cell Count, Humans, Lung Neoplasms, Microtubule-Associated Proteins, Mutation, Nuclear Proteins, Phosphorylation, Apoptosis, Neoplasm, Residual, Cell Cycle Proteins, Drug Resistance, Neoplasm, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Aurora Kinase A, ErbB Receptors
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