Effects of BRAF inhibitors on human melanoma tissue before treatment, early during treatment, and on progression

Authors

  • Georgina V. Long,

    Corresponding author
    1. Westmead Institute for Cancer Research, The University of Sydney, Sydney, NSW, Australia
    2. Discipline of Medicine, The University of Sydney, Sydney, NSW, Australia
    • Melanoma Institute Australia, Sydney, NSW, Australia
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    • GVL & JSW contributed equally to this work.
  • James S. Wilmott,

    1. Melanoma Institute Australia, Sydney, NSW, Australia
    2. Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia
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    • GVL & JSW contributed equally to this work.
  • Lauren E. Haydu,

    1. Melanoma Institute Australia, Sydney, NSW, Australia
    2. Discipline of Surgery, The University of Sydney, Sydney, NSW, Australia
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  • Varsha Tembe,

    1. Westmead Institute for Cancer Research, The University of Sydney, Sydney, NSW, Australia
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  • Raghwa Sharma,

    1. Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia
    2. Westmead Hospital, Sydney, NSW, Australia
    3. University of Western Sydney, Sydney, NSW, Australia
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  • Helen Rizos,

    1. Westmead Institute for Cancer Research, The University of Sydney, Sydney, NSW, Australia
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  • John F. Thompson,

    1. Melanoma Institute Australia, Sydney, NSW, Australia
    2. Discipline of Surgery, The University of Sydney, Sydney, NSW, Australia
    3. Royal Prince Alfred Hospital, Sydney, NSW, Australia
    4. Mater Hospital, Sydney, NSW, Australia
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  • Julie Howle,

    1. Westmead Institute for Cancer Research, The University of Sydney, Sydney, NSW, Australia
    2. Westmead Hospital, Sydney, NSW, Australia
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  • Richard A. Scolyer,

    1. Melanoma Institute Australia, Sydney, NSW, Australia
    2. Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia
    3. Royal Prince Alfred Hospital, Sydney, NSW, Australia
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  • Richard F. Kefford

    1. Melanoma Institute Australia, Sydney, NSW, Australia
    2. Westmead Institute for Cancer Research, The University of Sydney, Sydney, NSW, Australia
    3. Discipline of Medicine, The University of Sydney, Sydney, NSW, Australia
    4. Westmead Hospital, Sydney, NSW, Australia
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Correspondence G. V. Long, e-mail: georgina.long@sydney.edu.au

Summary

Selective BRAF inhibitors (BRAFi) are a standard of care for the treatment of BRAFV600-mutant metastatic melanoma. We analyzed a unique set of serial triplicate human metastatic melanoma tumor biopsies to identify biomarkers of BRAFi response and resistance. Morphologic features and immunohistochemical biomarkers were analyzed in 37 metastatic melanoma biopsies at pretreatment (PRE), early during treatment (EDT), and on progression (PROG) from 15 patients treated with a BRAFi and correlated with response and outcome. At EDT, proliferative markers decreased regardless of response, whereas markers of cell death increased in responders. High expression of nuclear p27 at baseline was the strongest predictor of a poorer OS and predicted worse response. The results show that BRAFi are universally antiproliferative, regardless of clinical response, whereas markers of cell death increased only in responders. The addition of therapies targeting the cell cycle machinery may improve the response and duration of BRAFi, and investigation of the mechanisms of apoptosis may provide additional therapeutic targets.

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