Klin Padiatr 2018; 230(03): 172-173
DOI: 10.1055/s-0038-1645015
Top 5 Cell biology and mechanisms of disease
Georg Thieme Verlag KG Stuttgart · New York

SMARCB1-Dependencies in Malignant Rhabdoid Tumours: A strategy for Pre-Clinical Therapeutic Target Identification in the Absence of Actionable Mutations

Authors

  • MA Finetti

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • R Ramli

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • J Hacking

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • D Ridgwell

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • MP Selby

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • Y Grabovska

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • A del-Carpio Pons

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • S Batting

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • JA Wood

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • JM Barker

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • A Smith

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • S Crosier

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • P O'Hare

    4   Department of Paediatric oncology, Great Ormond Street Hospital NHS trust, London, UK.

  • B Pizer

    5   Institute of Translational Medicine, University of Liverpool, Liverpool, UK

  • B Brennan

    6   Royal Manchester Children's Hospital and University of Manchester, Manchester, UK

  • S Lowis

    7   Royal Hospital for Children and Bristol Medical School, University of Bristol, UK

  • D Hargrave

    2   Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK
    4   Department of Paediatric oncology, Great Ormond Street Hospital NHS trust, London, UK.

  • J Anderson

    2   Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK

  • TS Jacques

    2   Developmental Biology and Cancer Programme, University College London Great Ormond Street Institute of Child Health, London, UK
    3   Department of Histopathology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

  • S Bailey

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • SC Clifford

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK

  • D Williamson

    1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
08. Mai 2018 (online)

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ATRTs have low mutation rates and few classically-actionable variants to direct molecularly targeted therapies; loss of SMARCB1 is the sole recurrent mutational event in > 90% of ATRTs. We have designed and implemented a genome-scale strategy for target identification and prioritization in tumors devoid of significant actionable mutations. Re-expression of SMARCB1 causes ATRT cells to cease proliferation and differentiate; we therefore hypothesized that identifying and counteracting critical downstream SMARCB1-dependent events represents a primary route to therapeutic intervention.

We identify such events using an integrated genome-wide approach encompassing genome-scale CRISPR/Cas9 functional screens (GeCKO screening; 122,411 sgRNAs) alongside expression/DNA methylation profiling of primary ATRTs and ATRT cells following SMARCB1 re-expression and/or treatment with demethylating agents. Cross-referencing these analyses, we use a rational selection algorithm, to identify critical tumorigenic genes/pathways and proceed to validate their ability to be targeted as therapeutic targets.

Our strategy identifies, ranks and prioritizes multiple SMARCB1-dependent pathways/genes functionally essential to ATRT, and characteristic of the primary tumour; including those previously described (Rb/CDK4/6, SHH, MYC), those less well evidenced (mTOR, TGF-β, HGF, Stat3/Jak) and novel SMARCB1-dependent synthetic lethalities (NuA4 complex, PIM1). We also describe the repressive genome-wide effect of SMARCB1 mutation on the transcriptome, through altered SWI/SNF binding, associated histone marks and localized hypermethylation and the therapeutic possibilities implied therein.

Data and web-based interactive analysis and visualization tools will be made publically available to help guide and benchmark future pre-clinical testing in ATRT. This study pinpoints SMARCB1-dependent therapeutic susceptibilities in MRTs with the capacity to inform future treatment strategies.