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A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities

Author

Listed:
  • Ravi S. Narayan

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Piet Molenaar

    (Academic Medical Center)

  • Jian Teng

    (Massachusetts General Hospital and Harvard Medical School)

  • Fleur M. G. Cornelissen

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Irene Roelofs

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Renee Menezes

    (Netherlands Cancer Institute)

  • Rogier Dik

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Tonny Lagerweij

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Yoran Broersma

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Naomi Petersen

    (Amsterdam UMC, location VUMC, Cancer Center
    Amsterdam UMC, location VUMC, Cancer Center)

  • Jhon Alexander Marin Soto

    (Amsterdam UMC, location VUMC, Cancer Center
    Amsterdam UMC, location VUMC, Cancer Center)

  • Eelke Brands

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Philip Kuiken

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Maria C. Lecca

    (Amsterdam UMC, location AMC, Cancer Center)

  • Kristiaan J. Lenos

    (Amsterdam UMC, location AMC, Cancer Center)

  • Sjors G. J. G. In ‘t Veld

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Wessel Wieringen

    (Amsterdam UMC, location VUMC)

  • Frederick F. Lang

    (The University of Texas MD Anderson Cancer Center)

  • Erik Sulman

    (NYU Langone Health)

  • Roel Verhaak

    (The Jackson Laboratory for Genomic Medicine)

  • Brigitta G. Baumert

    (Kantonsspital Graubünden, Loëstrasse 170)

  • Lucas J. A. Stalpers

    (Academic Medical Center)

  • Louis Vermeulen

    (Amsterdam UMC, location AMC, Cancer Center)

  • Colin Watts

    (University of Birmingham, Edgbaston)

  • David Bailey

    (IOTA Pharmaceuticals Ltd, St Johns Innovation Centre, Cowley Road)

  • Ben J. Slotman

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Rogier Versteeg

    (Academic Medical Center)

  • David Noske

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Peter Sminia

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Bakhos A. Tannous

    (Massachusetts General Hospital and Harvard Medical School)

  • Tom Wurdinger

    (Amsterdam UMC, location VUMC, Cancer Center)

  • Jan Koster

    (Academic Medical Center)

  • Bart A. Westerman

    (Amsterdam UMC, location VUMC, Cancer Center)

Abstract

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value.

Suggested Citation

  • Ravi S. Narayan & Piet Molenaar & Jian Teng & Fleur M. G. Cornelissen & Irene Roelofs & Renee Menezes & Rogier Dik & Tonny Lagerweij & Yoran Broersma & Naomi Petersen & Jhon Alexander Marin Soto & Eel, 2020. "A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16735-2
    DOI: 10.1038/s41467-020-16735-2
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    Cited by:

    1. Mohieddin Jafari & Mehdi Mirzaie & Jie Bao & Farnaz Barneh & Shuyu Zheng & Johanna Eriksson & Caroline A. Heckman & Jing Tang, 2022. "Bipartite network models to design combination therapies in acute myeloid leukaemia," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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