Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
All data generated or analyzed during this study are included in this published article and its supplementary information files. Cell lines generated in this study are available upon reasonable request from the authors.
References
Jänne, P. A. et al. AZD9291 in EGFR inhibitor-resistant non-small-cell lung cancer. N. Engl. J. Med. 372, 1689–1699 (2015).
Sequist, L. V. et al. Rociletinib in EGFR-mutated non-small-cell lung cancer. N. Engl. J. Med. 372, 1700–1709 (2015).
Rosell, R. et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 13, 239–246 (2012).
Sequist, L. V. et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011).
Blakely, C. M. et al. Evolution and clinical impact of co-occurring genetic alterations in advanced-stage EGFR-mutant lung cancers. Nat. Genet. 49, 1693–1704 (2017).
Burrell, R. A. & Swanton, C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol. Oncol. 8, 1095–1111 (2014).
Chabon, J. J. et al. Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients. Nat. Commun. 7, 11815 (2016).
Yang, Z. et al. Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients. Clin. Cancer Res. 24, 3097–3107 (2018).
Bivona, T. G. & Doebele, R. C. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat. Med. 22, 472–478 (2016).
Hata, A. N. et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat. Med. 22, 262–269 (2016).
Ramirez, M. et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat. Commun. 7, 10690 (2016).
Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).
Kim, T. M. et al. Mechanisms of acquired resistance to AZD9291: a mutation-selective, irreversible EGFR inhibitor. J. Thorac. Oncol. 10, 1736–1744 (2015).
Li, L. et al. Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: a case report. Oncotarget 8, 18609–18614 (2017).
Piotrowska, Z. et al. Heterogeneity underlies the emergence of EGFR T790 wild-type clones following treatment of T790M-positive cancers with a third-generation EGFR inhibitor. Cancer Discov. 5, 713–722 (2015).
Thress, K. S. et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat. Med. 21, 560–562 (2015).
Niederst, M. J. & Engelman, J. A. Bypass mechanisms of resistance to receptor tyrosine kinase inhibition in lung cancer. Sci. Signal. 6, re6 (2013).
Bivona, T. G. et al. FAS and NF-κB signalling modulate dependence of lung cancers on mutant EGFR. Nature 471, 523–526 (2011).
Blakely, C. M. et al. NF-κB-activating complex engaged in response to EGFR oncogene inhibition drives tumor cell survival and residual disease in lung cancer. Cell Rep. 11, 98–110 (2015).
Shien, K. et al. Acquired resistance to EGFR inhibitors is associated with a manifestation of stem cell-like properties in cancer cells. Cancer Res. 73, 3051–3061 (2013).
Chen, J. et al. AURKA upregulation plays a role in fibroblast-reduced gefitinib sensitivity in the NSCLC cell line HCC827. Oncol. Rep. 33, 1860–1866 (2015).
Eberlein, C. A. et al. Acquired resistance to the mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling in preclinical models. Cancer Res. 75, 2489–2500 (2015).
Karaman, M. W. et al. A quantitative analysis of kinase inhibitor selectivity. Nat. Biotechnol. 26, 127–132 (2008).
Fu, J., Bian, M., Jiang, Q. & Zhang, C. Roles of Aurora kinases in mitosis and tumorigenesis. Mol. Cancer Res. 5, 1–10 (2007).
Sharifnia, T. et al. Genetic modifiers of EGFR dependence in non-small cell lung cancer. Proc. Natl. Acad. Sci. USA 111, 18661–18666 (2014).
Nikonova, A. S., Astsaturov I.Serebriiskii, I. G., Dunbrack, R. L.Jr. & Golemis, E. A. Aurora A kinase (AURKA) in normal and pathological cell division. Cell. Mol. Life Sci. 70, 661–687 (2013).
Stewart, S. & Fang, G. Anaphase-promoting complex/cyclosome controls the stability of TPX2 during mitotic exit. Mol. Cell. Biol. 25, 10516–10527 (2005).
Zhou, Y., Ching, Y. P., Chun, A. C. & Jin, D. Y. Nuclear localization of the cell cycle regulator CDH1 and its regulation by phosphorylation. J. Biol. Chem. 278, 12530–12536 (2003).
Ercan, D. et al. Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors. Cancer Discov. 2, 934–947 (2012).
Costa, D. B. et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med. 4, 1669–1679 (2007).
Cragg, M. S., Kuroda, J., Puthalakath, H., Huang, D. C. & Strasser, A. Gefitinib-induced killing of NSCLC cell lines expressing mutant EGFR requires BIM and can be enhanced by BH3 mimetics. PLoS Med. 4, 1681–1689 (2007).
Hübner, A., Barrett, T., Flavell, R. A. & Davis, R. J. Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol. Cell 30, 415–425 (2008).
Moustafa-Kamal, M., Gamache, I., Lu, Y., Li, S. & Teodoro, J. G. BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1. Cell Death Differ. 20, 1393–1403 (2013).
Anand, S., Penrhyn-Lowe, S. & Venkitaraman, A. R. AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell. 3, 51–62 (2003).
Gruss, O. J. et al. Chromosome-induced microtubule assembly mediated by TPX2 is required for spindle formation in HeLa cells. Nat. Cell Biol. 4, 871–879 (2002).
Lee, A. J. et al. Chromosomal instability confers intrinsic multidrug resistance. Cancer Res. 71, 1858–1870 (2011).
D’Assoro, A. B. et al. The mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα+ breast cancer cells. Oncogene 33, 599–610 (2014).
Lee, C. K. et al. Clinical and molecular characteristics associated with survival among patients treated with checkpoint inhibitors for advanced non-small cell lung carcinoma: a systematic review and meta-analysis. JAMA Oncol. 4, 210–216 (2018).
Bavetsias, V. & Linardopoulos, S. Aurora kinase inhibitors: currents status and outlook. Front. Oncol. 5, 278 (2015).
Melichar, B. et al. Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: a five-arm phase 2 study. Lancet Oncol. 16, 395–405 (2015).
Chou, T. C. Drug combination studies and their synergy quantification using the Chou–Talalay method. Cancer Res. 70, 440–446 (2010).
Varghese, F., Bukhari, A. B., Malhotra, R. & De, A. IHC Profiler: an open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE 9, e96801 (2014).
Acknowledgements
We thank members of the Bandyopadhyay laboratory for helpful discussions and technical assistance. We also thank J. Gordon from the LCA microscopy core for technical assistance and reagents. This work was supported by National Cancer Institute grant nos. U01CA168370 (S.B.), NIGMS R01GM107671 (S.B.), R01CA169338 (T.G.B) and U54CA224081 (S.B., T.G.B).
Author information
Authors and Affiliations
Contributions
Project conception: K.N.S. and S.B. Performance of experiments: K.N.S., R.B., J.W., J. Rotow, J. Rohrberg, V.E.W., H.J.D., J.G., V.O., G.H., M.M.M., A.M., J.K., H.J.H., L.R. and G.K. Data analysis and interpretation: K.N.S., H.J.D., S.K., A.K., S.D. and G.K. Manuscript writing: K.N.S. and S.B. Manuscript finalization: all authors. Study supervision: T.C.H., A.D.S., F.M., A.G., C.M.B., T.G.B and S.B. Funding: S.B.
Corresponding author
Ethics declarations
Competing interests
H.J.H., L.R., A.D.S. and T.C.H. are employees of Clovis Oncology. S.B. recieves funding and/or has a consultancy relationship with Ideaya Biosciences and Pfizer.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–11
Supplementary Table 1
Results of drug synergy screen
Supplementary Table 2
Mitotic defects after EGFR TKI treatment
Rights and permissions
About this article
Cite this article
Shah, K.N., Bhatt, R., Rotow, J. et al. Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer. Nat Med 25, 111–118 (2019). https://doi.org/10.1038/s41591-018-0264-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41591-018-0264-7
This article is cited by
-
AURKA inhibition induces Ewing’s sarcoma apoptosis and ferroptosis through NPM1/YAP1 axis
Cell Death & Disease (2024)
-
Protein kinase D2-Aurora kinase A-ERK1/2 signalling axis drives neuroendocrine differentiation of epithelial ovarian cancer
Molecular and Cellular Biochemistry (2024)
-
Predicting drug response from single-cell expression profiles of tumours
BMC Medicine (2023)
-
Exploring potential molecular resistance and clonal evolution in advanced HER2-positive gastric cancer under trastuzumab therapy
Oncogenesis (2023)
-
A new wave of innovations within the DNA damage response
Signal Transduction and Targeted Therapy (2023)