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.

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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.

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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

Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA

    • Khyati N. Shah
    • , Roma Bhatt
    • , Hayley J. Donnella
    • , Swati Kaushik
    • , Angel Ku
    •  & Sourav Bandyopadhyay
  2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA

    • Khyati N. Shah
    • , Roma Bhatt
    • , Julia Rotow
    • , Julia Rohrberg
    • , Victor Olivas
    • , Victoria E. Wang
    • , Golzar Hemmati
    • , Maria M. Martins
    • , Ashley Maynard
    • , Jacqueline Galeas
    • , Hayley J. Donnella
    • , Swati Kaushik
    • , Angel Ku
    • , Frank McCormick
    • , Andrei Goga
    • , Collin M. Blakely
    • , Trever G. Bivona
    •  & Sourav Bandyopadhyay
  3. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    • Julia Rotow
    • , Julia Rohrberg
    • , Victor Olivas
    • , Golzar Hemmati
    • , Maria M. Martins
    • , Ashley Maynard
    • , Collin M. Blakely
    •  & Trever G. Bivona
  4. Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA

    • Jonathan Kuhn
    • , Sophie Dumont
    •  & Andrei Goga
  5. Department of Pathology, University of California, San Francisco, San Francisco, CA, USA

    • Gregor Krings
  6. Clovis Oncology, Inc., Boulder, CO, USA

    • Henry J. Haringsma
    • , Liliane Robillard
    • , Andrew D. Simmons
    •  & Thomas C. Harding

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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.

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.

Corresponding author

Correspondence to Sourav Bandyopadhyay.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–11

  2. Reporting Summary

  3. Supplementary Table 1

    Results of drug synergy screen

  4. Supplementary Table 2

    Mitotic defects after EGFR TKI treatment

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DOI

https://doi.org/10.1038/s41591-018-0264-7