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HER2-positive breast-cancer cell lines are sensitive to KDM5 inhibition: definition of a gene-expression model for the selection of sensitive cases

Oncogene (2018) | Download Citation

Abstract

Targeting of histone methylation has therapeutic potential in oncology. Here, we provide proof-of-principle that pharmacological inhibition of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2+ breast cancer. The anti-proliferative effects of the prototype of a new class of selective KDM5-inhibitors (KDM5-inh1) are evaluated in 40 cell lines, recapitulating the heterogeneity of breast cancer. This analysis demonstrates that HER2+ cells are particularly sensitive to KDM5 inhibition. The results are confirmed in an appropriate in vivo model with a close structural analog (KDM5-inh1A). RNA-seq data obtained in HER2+ BT-474 cells exposed to KDM5-Inh1 indicate that the compound alters expression of numerous genes downstream of the ERBB2 gene-product, HER2. In selected HER2-positive breast-cancer cells, we demonstrate synergistic interactions between KDM5-inh1 and HER2-targeting agents (trastuzumab and lapatinib). In addition, HER2+ cell lines with innate and acquired resistance to trastuzumab show sensitivity to KDM5-inh1. The levels of KDM5A/B/C proteins, which are selectively targeted by the agent, have no significant association with KDM5-inh1 responsiveness across our panel of breast-cancer cell lines, suggesting the existence of other determinants of sensitivity. Using RNA-seq data of the breast-cancer cell lines we generate a gene-expression model that is a robust predictor of KDM5-inh1 sensitivity. In a test set of breast cancers, this model predicts sensitivity to the compound in a large fraction of HER2+ tumors. In conclusion, KDM5 inhibition has potential in the treatment of HER2+ breast cancer and our gene-expression model can be developed into a diagnostic tool for the selection of patients.

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Acknowledgements

Grants from the Associazione Italiana per la Ricerca contro il Cancro (AIRC) and the Fondazione Italo Monzino to Enrico Garattini were fundamental for the completion of this work. We would like to acknowledge the help of Mr. Alessandro Soave for the artwork and Laura Pasetto for the densitometric analyses.

Authors contribution

GP and AZ performed the experimental work involving the use of cell lines; MB and MF were involved in the computational analysis of the gene-expression datasets; PU developed the mathematical algorithms and models necessary for the development of the KDM5I-score; KH, PS, and LOS were involved in the design and conduction of the in vivo experiments; MT supervised some of the phases of the work and wrote the manuscript; EG and RMN designed and supervised the entire study and wrote the manuscript.

Author information

Author notes

  1. These authors share the first authorship: Gabriela Paroni, Marco Bolis

  2. These authors share the last authorship: Mineko Terao, Enrico Garattini

Affiliations

  1. Laboratory of Molecular Biology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via La Masa 19, 20157, Milano, Italy

    • Gabriela Paroni
    • , Marco Bolis
    • , Adriana Zanetti
    • , Maddalena Fratelli
    • , Mineko Terao
    •  & Enrico Garattini
  2. Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, via La Masa 19, 20157, Milano, Italy

    • Paolo Ubezio
  3. Biotech Research and Innovation Centre (BRIC), University of Copenhagen Ole Maaløes Vej 5, 2200, Copenhagen, Denmark

    • Kristian Helin
  4. The Novo Nordisk Foundation for Stem Cell Biology, University of Copenhagen, Blegdamsvej 3, 2200, Copenhagen, Denmark

    • Kristian Helin
  5. Drug Discovery, Bayer AG, Müllerstr. 178, 13353, Berlin, Germany

    • Peter Staller
  6. CV Research, Global Drug Discovery, Novo Nordisk, Denmark

    • Lars Ole Gerlach
  7. Gilead Sciences Inc., Foster City, CA, 94404, USA

    • Richard M. Neve

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Conflict of interest

Richard M. Neve is an employee of Gilead Sciences which developed and patented the proprietary KDM5 inhibitors used in the present study. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Enrico Garattini.

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DOI

https://doi.org/10.1038/s41388-018-0620-6