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The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status

Author

Listed:
  • Ricky M. Trigg

    (University of Cambridge
    Medicinal Science & Technology)

  • Liam C. Lee

    (University of Cambridge
    Amgen)

  • Nina Prokoph

    (University of Cambridge)

  • Leila Jahangiri

    (University of Cambridge)

  • C. Patrick Reynolds

    (Cancer Center, Texas Tech University Health Sciences Center School of Medicine)

  • G. A. Amos Burke

    (Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus)

  • Nicola A. Probst

    (University of Cambridge)

  • Miaojun Han

    (University of Cambridge
    OncoSec)

  • Jamie D. Matthews

    (University of Cambridge)

  • Hong Kai Lim

    (University of Cambridge)

  • Eleanor Manners

    (University of Cambridge)

  • Sonia Martinez

    (Spanish National Cancer Research Centre (CNIO))

  • Joaquin Pastor

    (Spanish National Cancer Research Centre (CNIO))

  • Carmen Blanco-Aparicio

    (Spanish National Cancer Research Centre (CNIO))

  • Olaf Merkel

    (Medical University of Vienna)

  • Ines Garces los Fayos Alonso

    (Medical University of Vienna)

  • Petra Kodajova

    (University of Veterinary Medicine Vienna)

  • Simone Tangermann

    (University of Veterinary Medicine Vienna)

  • Sandra Högler

    (University of Veterinary Medicine Vienna)

  • Ji Luo

    (National Cancer Institute, National Institutes of Health)

  • Lukas Kenner

    (Medical University of Vienna
    University of Veterinary Medicine Vienna
    Medical University of Vienna)

  • Suzanne D. Turner

    (University of Cambridge)

Abstract

Resistance to anaplastic lymphoma kinase (ALK)-targeted therapy in ALK-positive non-small cell lung cancer has been reported, with the majority of acquired resistance mechanisms relying on bypass signaling. To proactively identify resistance mechanisms in ALK-positive neuroblastoma (NB), we herein employ genome-wide CRISPR activation screens of NB cell lines treated with brigatinib or ceritinib, identifying PIM1 as a putative resistance gene, whose high expression is associated with high-risk disease and poor survival. Knockdown of PIM1 sensitizes cells of differing MYCN status to ALK inhibitors, and in patient-derived xenografts of high-risk NB harboring ALK mutations, the combination of the ALK inhibitor ceritinib and PIM1 inhibitor AZD1208 shows significantly enhanced anti-tumor efficacy relative to single agents. These data confirm that PIM1 overexpression decreases sensitivity to ALK inhibitors in NB, and suggests that combined front-line inhibition of ALK and PIM1 is a viable strategy for the treatment of ALK-positive NB independent of MYCN status.

Suggested Citation

  • Ricky M. Trigg & Liam C. Lee & Nina Prokoph & Leila Jahangiri & C. Patrick Reynolds & G. A. Amos Burke & Nicola A. Probst & Miaojun Han & Jamie D. Matthews & Hong Kai Lim & Eleanor Manners & Sonia Mar, 2019. "The targetable kinase PIM1 drives ALK inhibitor resistance in high-risk neuroblastoma independent of MYCN status," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13315-x
    DOI: 10.1038/s41467-019-13315-x
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    Cited by:

    1. Karin Schmelz & Joern Toedling & Matt Huska & Maja C. Cwikla & Louisa-Marie Kruetzfeldt & Jutta Proba & Peter F. Ambros & Inge M. Ambros & Sengül Boral & Marco Lodrini & Celine Y. Chen & Martin Burker, 2021. "Spatial and temporal intratumour heterogeneity has potential consequences for single biopsy-based neuroblastoma treatment decisions," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    2. Perla Pucci & Liam C. Lee & Miaojun Han & Jamie D. Matthews & Leila Jahangiri & Michaela Schlederer & Eleanor Manners & Annabel Sorby-Adams & Joshua Kaggie & Ricky M. Trigg & Christopher Steel & Lucy , 2024. "Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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