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Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma

Author

Listed:
  • Lorey K. Smith

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Tiffany Parmenter

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Margarete Kleinschmidt

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Eric P. Kusnadi

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Jian Kang

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Claire A. Martin

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Peter Lau

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Riyaben Patel

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Julie Lorent

    (Karolinska Institutet)

  • David Papadopoli

    (McGill University)

  • Anna Trigos

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Teresa Ward

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Aparna D. Rao

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Emily J. Lelliott

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Karen E. Sheppard

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

  • David Goode

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Rodney J. Hicks

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Tony Tiganis

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne
    Monash University)

  • Kaylene J. Simpson

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Ola Larsson

    (McGill University)

  • Benjamin Blythe

    (Cancer Research Division, Peter MacCallum Cancer Centre)

  • Carleen Cullinane

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Vihandha O. Wickramasinghe

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne)

  • Richard B. Pearson

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

  • Grant A. McArthur

    (Cancer Research Division, Peter MacCallum Cancer Centre
    University of Melbourne
    University of Melbourne)

Abstract

Despite the success of therapies targeting oncogenes in cancer, clinical outcomes are limited by residual disease that ultimately results in relapse. This residual disease is often characterized by non-genetic adaptive resistance, that in melanoma is characterised by altered metabolism. Here, we examine how targeted therapy reprograms metabolism in BRAF-mutant melanoma cells using a genome-wide RNA interference (RNAi) screen and global gene expression profiling. Using this systematic approach we demonstrate post-transcriptional regulation of metabolism following BRAF inhibition, involving selective mRNA transport and translation. As proof of concept we demonstrate the RNA processing kinase U2AF homology motif kinase 1 (UHMK1) associates with mRNAs encoding metabolism proteins and selectively controls their transport and translation during adaptation to BRAF-targeted therapy. UHMK1 inactivation induces cell death by disrupting therapy induced metabolic reprogramming, and importantly, delays resistance to BRAF and MEK combination therapy in multiple in vivo models. We propose selective mRNA processing and translation by UHMK1 constitutes a mechanism of non-genetic resistance to targeted therapy in melanoma by controlling metabolic plasticity induced by therapy.

Suggested Citation

  • Lorey K. Smith & Tiffany Parmenter & Margarete Kleinschmidt & Eric P. Kusnadi & Jian Kang & Claire A. Martin & Peter Lau & Riyaben Patel & Julie Lorent & David Papadopoli & Anna Trigos & Teresa Ward &, 2022. "Adaptive translational reprogramming of metabolism limits the response to targeted therapy in BRAFV600 melanoma," Nature Communications, Nature, vol. 13(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28705-x
    DOI: 10.1038/s41467-022-28705-x
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