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Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies

Author

Listed:
  • Valentina Cordo’

    (Princess Máxima Center for Pediatric Oncology)

  • Mariska T. Meijer

    (Princess Máxima Center for Pediatric Oncology)

  • Rico Hagelaar

    (Princess Máxima Center for Pediatric Oncology)

  • Richard R. Goeij-de Haas

    (Amsterdam University Medical Centers, VU University
    Amsterdam University Medical Centers, VU University)

  • Vera M. Poort

    (Princess Máxima Center for Pediatric Oncology)

  • Alex A. Henneman

    (Amsterdam University Medical Centers, VU University
    Amsterdam University Medical Centers, VU University)

  • Sander R. Piersma

    (Amsterdam University Medical Centers, VU University
    Amsterdam University Medical Centers, VU University)

  • Thang V. Pham

    (Amsterdam University Medical Centers, VU University
    Amsterdam University Medical Centers, VU University)

  • Koichi Oshima

    (Columbia University Medical Center)

  • Adolfo A. Ferrando

    (Columbia University Medical Center)

  • Guido J. R. Zaman

    (Oncolines B.V.)

  • Connie R. Jimenez

    (Amsterdam University Medical Centers, VU University
    Amsterdam University Medical Centers, VU University)

  • Jules P. P. Meijerink

    (Princess Máxima Center for Pediatric Oncology
    Acerta Pharma (member of the AstraZeneca group))

Abstract

Protein kinase inhibitors are amongst the most successful cancer treatments, but targetable kinases activated by genomic abnormalities are rare in T cell acute lymphoblastic leukemia. Nevertheless, kinases can be activated in the absence of genetic defects. Thus, phosphoproteomics can provide information on pathway activation and signaling networks that offer opportunities for targeted therapy. Here, we describe a mass spectrometry-based global phosphoproteomic profiling of 11 T cell acute lymphoblastic leukemia cell lines to identify targetable kinases. We report a comprehensive dataset consisting of 21,000 phosphosites on 4,896 phosphoproteins, including 217 kinases. We identify active Src-family kinases signaling as well as active cyclin-dependent kinases. We validate putative targets for therapy ex vivo and identify potential combination treatments, such as the inhibition of the INSR/IGF-1R axis to increase the sensitivity to dasatinib treatment. Ex vivo validation of selected drug combinations using patient-derived xenografts provides a proof-of-concept for phosphoproteomics-guided design of personalized treatments.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28682-1
    DOI: 10.1038/s41467-022-28682-1
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    References listed on IDEAS

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    1. Martin Frejno & Chen Meng & Benjamin Ruprecht & Thomas Oellerich & Sebastian Scheich & Karin Kleigrewe & Enken Drecoll & Patroklos Samaras & Alexander Hogrebe & Dominic Helm & Julia Mergner & Jana Zec, 2020. "Proteome activity landscapes of tumor cell lines determine drug responses," Nature Communications, Nature, vol. 11(1), pages 1-12, December.
    2. Gannie Tzoneva & Chelsea L. Dieck & Koichi Oshima & Alberto Ambesi-Impiombato & Marta Sánchez-Martín & Chioma J. Madubata & Hossein Khiabanian & Jiangyan Yu & Esme Waanders & Ilaria Iacobucci & Maria , 2018. "Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia," Nature, Nature, vol. 553(7689), pages 511-514, January.
    3. 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.
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