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Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

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Listed:
  • Georgina V. Long

    (Melanoma Institute Australia
    Discipline of Medicine, Sydney Medical School, The University of Sydney
    Mater Hospital)

  • Carina Fung

    (Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University
    Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital)

  • Alexander M. Menzies

    (Melanoma Institute Australia
    Discipline of Medicine, Sydney Medical School, The University of Sydney
    Crown Princess Mary Cancer Centre, Westmead Hospital)

  • Gulietta M. Pupo

    (Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital)

  • Matteo S. Carlino

    (Melanoma Institute Australia
    Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital
    Crown Princess Mary Cancer Centre, Westmead Hospital)

  • Jessica Hyman

    (Melanoma Institute Australia
    Royal Prince Alfred Hospital)

  • Hamideh Shahheydari

    (Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University
    Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital)

  • Varsha Tembe

    (Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital)

  • John F. Thompson

    (Melanoma Institute Australia
    Discipline of Surgery, Sydney Medical School, The University of Sydney
    Royal Prince Alfred Hospital)

  • Robyn P. Saw

    (Melanoma Institute Australia
    Discipline of Surgery, Sydney Medical School, The University of Sydney
    Royal Prince Alfred Hospital)

  • Julie Howle

    (Melanoma Institute Australia
    Discipline of Surgery, Sydney Medical School, The University of Sydney
    Crown Princess Mary Cancer Centre, Westmead Hospital)

  • Nicholas K. Hayward

    (Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston)

  • Peter Johansson

    (Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston)

  • Richard A. Scolyer

    (Melanoma Institute Australia
    Royal Prince Alfred Hospital
    Discipline of Pathology, Sydney Medical School, The University of Sydney)

  • Richard F. Kefford

    (Melanoma Institute Australia
    Discipline of Medicine, Sydney Medical School, The University of Sydney
    Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University
    Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital)

  • Helen Rizos

    (Precision Cancer Therapy Laboratory, Australian School of Advanced Medicine, Macquarie University
    Westmead Institute for Cancer Research, The University of Sydney at Westmead Millennium Institute, Westmead Hospital)

Abstract

One-third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAFV600-mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the synonymous MEK1C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.

Suggested Citation

  • Georgina V. Long & Carina Fung & Alexander M. Menzies & Gulietta M. Pupo & Matteo S. Carlino & Jessica Hyman & Hamideh Shahheydari & Varsha Tembe & John F. Thompson & Robyn P. Saw & Julie Howle & Nich, 2014. "Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma," Nature Communications, Nature, vol. 5(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6694
    DOI: 10.1038/ncomms6694
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    Cited by:

    1. Jiaxin Liang & Deyang Yu & Chi Luo & Christopher Bennett & Mark Jedrychowski & Steve P. Gygi & Hans R. Widlund & Pere Puigserver, 2023. "Epigenetic suppression of PGC1α (PPARGC1A) causes collateral sensitivity to HMGCR-inhibitors within BRAF-treatment resistant melanomas," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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