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Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures

Author

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  • Giulia Franciosa

    (University of Copenhagen)

  • Jos G. A. Smits

    (University of Copenhagen
    Radboud University)

  • Sonia Minuzzo

    (University of Padova)

  • Ana Martinez-Val

    (University of Copenhagen)

  • Stefano Indraccolo

    (University of Padova
    Veneto Institute of Oncology IOV – IRCCS)

  • Jesper V. Olsen

    (University of Copenhagen)

Abstract

Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.

Suggested Citation

  • Giulia Franciosa & Jos G. A. Smits & Sonia Minuzzo & Ana Martinez-Val & Stefano Indraccolo & Jesper V. Olsen, 2021. "Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22787-9
    DOI: 10.1038/s41467-021-22787-9
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    Cited by:

    1. Valentina Cordo’ & Mariska T. Meijer & Rico Hagelaar & Richard R. Goeij-de Haas & Vera M. Poort & Alex A. Henneman & Sander R. Piersma & Thang V. Pham & Koichi Oshima & Adolfo A. Ferrando & Guido J. R, 2022. "Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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