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Abstract

Triple-negative breast cancer (TNBC), in which cells lack expression of the estrogen receptor (ER), the progesterone receptor (PR) and the ERBB2 (also known as HER2) receptor, is the breast cancer subtype with the poorest outcome1. No targeted therapy is available against this subtype of cancer owing to a lack of validated molecular targets. We previously reported that signaling involving MYC—an essential, pleiotropic transcription factor that regulates the expression of hundreds of genes—is disproportionally higher in triple-negative (TN) tumors than in receptor-positive (RP) tumors2. Direct inhibition of the oncogenic transcriptional activity of MYC has been challenging to achieve3. Here, by conducting a shRNA screen targeting the kinome, we identified PIM1, a non-essential serine–threonine kinase, in a synthetic lethal interaction with MYC. PIM1 expression was higher in TN tumors than in RP tumors and was associated with poor prognosis in patients with hormone- and HER2-negative tumors. Small-molecule PIM kinase inhibitors halted the growth of human TN tumors with elevated MYC expression in patient-derived tumor xenograft (PDX) and MYC-driven transgenic mouse models of breast cancer by inhibiting the oncogenic transcriptional activity of MYC and restoring the function of the endogenous cell cycle inhibitor, p27. Our findings warrant clinical evaluation of PIM kinase inhibitors in patients with TN tumors that have elevated MYC expression.

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Acknowledgements

This work was supported in part by grants from the US National Institutes of Health (K99CA175700 (D.H.), R00CA175700 (D.H.), 5T32DK007418 (R.C.), K99CA181490 (K.K.), ES019458 (P.Y. and Z.W.), U01CA168370 (M.T.M.), P30DK63720 (M.T.M.), R01CA180039 (Z.W.) and R01CA170447 (A.G.)), the Susan G. Komen Foundation (PDF15331114; J.R.), the UCSF Program for Breakthrough Biomedical Research (M.T.M.), an Innovative, Developmental, and Exploratory Award from the California Breast Cancer Research Program (17lB-0024; A.G.), an Era of Hope Scholar Award from the CDMRP Breast Cancer Research Program (W81XWH-12-1-0272 and W81XWH-16-1-0603; both to A.G.), an LLS Scholar Award (A.G.), a V-Foundation Award (A.G.), the Breast Cancer Research Foundation (H.S.R. and A.G.) and the Northwestern Medicine Catalyst Funds (D.H.). The authors thank A. Welm for her guidance with the use of the patient-derived orthotopic tumor xenograft models, J.W. Smyth for his assistance with the generation of the transgenic breast cancer cell lines, and D.B. Udy, C.L. Hueschen and A. Vasilopoulos for their assistance with microscopy. We thank S. Samson, C. Baas, H. Klein-Connolly and D. Roth for consumer advocacy support and feedback related to this project, and J.M. Bishop for his insights into the project and his mentorship to D.H.

Author information

Author notes

    • Alicia Y Zhou
    • , Sanjeev Balakrishnan
    • , Alexandra N Corella
    • , Henok Eyob
    • , Kai Kessenbrock
    • , Devon A Lawson
    • , Brittany N Anderton
    •  & Alexey V Bazarov

    Present addresses: Color Genomics, Burlingame, California, USA (A.Y.Z.); Dovetail Genomics, Santa Cruz, California, USA (S.B.); Molecular and Cellular Biology Graduate Program, University of Washington, Seattle, Washington, USA and Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA (A.N.C.); Boston Consulting Group, New Jersey, USA (H.E.); Department of Biological Chemistry, School of Medicine, University of California, Irvine, California, USA (K.K.); Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California, USA (D.A.L.); Biology Education Research Group, University of California, Davis, Davis, California, USA (B.N.A.); Cypre, Inc., San Francisco, California, USA (A.V.B.).

Affiliations

  1. Department of Cell and Tissue Biology, University of California, San Francisco (UCSF), San Francisco, California, USA.

    • Dai Horiuchi
    • , Roman Camarda
    • , Alicia Y Zhou
    • , Olga Momcilovic
    • , Sanjeev Balakrishnan
    • , Alexandra N Corella
    • , Henok Eyob
    • , Brittany N Anderton
    • , Julia Rohrberg
    •  & Andrei Goga
  2. Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California, USA.

    • Dai Horiuchi
    • , Zena Werb
    •  & Andrei Goga
  3. Department of Pharmacology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.

    • Dai Horiuchi
    • , Lindsey A Marsh
    •  & Ratika Kunder
  4. Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA.

    • Dai Horiuchi
    • , Lindsey A Marsh
    •  & Ratika Kunder
  5. Department of Surgery, University of California, San Francisco, San Francisco, California, USA.

    • Christina Yau
  6. Cancer and Developmental Therapeutics Program, Buck Institute for Research on Aging, Novato, California, USA.

    • Christina Yau
  7. Department of Anatomy, University of California, San Francisco, San Francisco, California, USA.

    • Kai Kessenbrock
    • , Devon A Lawson
    •  & Zena Werb
  8. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California, USA.

    • Alexey V Bazarov
    •  & Paul Yaswen
  9. Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, California, USA.

    • Michael T McManus
  10. Department of Medicine, University of California, San Francisco, San Francisco, California, USA.

    • Hope S Rugo
    •  & Andrei Goga

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Contributions

D.H. and A.G. conceived the project; D.H. designed and executed the shRNA screen and the subsequent biological experiments, analyzed the data and wrote the manuscript; A.V.B., M.T.M. and P.Y. provided materials for, and contributed to, designing and executing the screen; C.Y. and S.B. performed bioinformatics analyses; D.A.L., H.S.R. and Z.W. provided materials for, and contributed to, designing and executing the animal experiments involving the patient-derived orthotopic tumor xenografts; R.C., A.Y.Z., A.N.C., H.E., K.K., L.A.M., B.N.A., J.R. and R.K. contributed to executing the biological experiments; R.C., A.Y.Z., C.Y., S.B., L.A.M., B.N.A., P.Y., Z.W., O.M. and A.G. participated in the writing of the manuscript; and A.G. supervised the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Dai Horiuchi or Andrei Goga.

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DOI

https://doi.org/10.1038/nm.4213

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