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Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

Author

Listed:
  • Judith Müller

    (The Netherlands Cancer Institute)

  • Oscar Krijgsman

    (The Netherlands Cancer Institute)

  • Jennifer Tsoi

    (David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA))

  • Lidia Robert

    (David Geffen School of Medicine at University of California, Los Angeles (UCLA))

  • Willy Hugo

    (David Geffen School of Medicine at University of California, Los Angeles (UCLA))

  • Chunying Song

    (David Geffen School of Medicine at University of California, Los Angeles (UCLA))

  • Xiangju Kong

    (David Geffen School of Medicine at University of California, Los Angeles (UCLA))

  • Patricia A. Possik

    (The Netherlands Cancer Institute)

  • Paulien D. M. Cornelissen-Steijger

    (The Netherlands Cancer Institute)

  • Marnix H Geukes Foppen

    (The Netherlands Cancer Institute)

  • Kristel Kemper

    (The Netherlands Cancer Institute)

  • Colin R. Goding

    (Ludwig Institute for Cancer Research, University of Oxford)

  • Ultan McDermott

    (Wellcome Trust Sanger Institute, Genome Campus)

  • Christian Blank

    (The Netherlands Cancer Institute)

  • John Haanen

    (The Netherlands Cancer Institute)

  • Thomas G. Graeber

    (David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA)
    UCLA Metabolomics Center, Crump Institute for Molecular Imaging, California Nanosystems Institute, UCLA
    Jonsson Comprehensive Cancer Center (JCCC))

  • Antoni Ribas

    (David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA)
    David Geffen School of Medicine at University of California, Los Angeles (UCLA)
    Jonsson Comprehensive Cancer Center (JCCC))

  • Roger S. Lo

    (David Geffen School of Medicine at University of California, University of California, Los Angeles (UCLA)
    David Geffen School of Medicine at University of California, Los Angeles (UCLA)
    Jonsson Comprehensive Cancer Center (JCCC))

  • Daniel S. Peeper

    (The Netherlands Cancer Institute)

Abstract

Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas.

Suggested Citation

  • Judith Müller & Oscar Krijgsman & Jennifer Tsoi & Lidia Robert & Willy Hugo & Chunying Song & Xiangju Kong & Patricia A. Possik & Paulien D. M. Cornelissen-Steijger & Marnix H Geukes Foppen & Kristel , 2014. "Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma," Nature Communications, Nature, vol. 5(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6712
    DOI: 10.1038/ncomms6712
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    Cited by:

    1. Anastasia Samarkina & Markus Kirolos Youssef & Paola Ostano & Soumitra Ghosh & Min Ma & Beatrice Tassone & Tatiana Proust & Giovanna Chiorino & Mitchell P. Levesque & Sandro Goruppi & Gian Paolo Dotto, 2023. "Androgen receptor is a determinant of melanoma targeted drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Claudia Capparelli & Timothy J. Purwin & McKenna Glasheen & Signe Caksa & Manoela Tiago & Nicole Wilski & Danielle Pomante & Sheera Rosenbaum & Mai Q. Nguyen & Weijia Cai & Janusz Franco-Barraza & Ric, 2022. "Targeting SOX10-deficient cells to reduce the dormant-invasive phenotype state in melanoma," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    3. Miles C. Andrews & Junna Oba & Chang-Jiun Wu & Haifeng Zhu & Tatiana Karpinets & Caitlin A. Creasy & Marie-Andrée Forget & Xiaoxing Yu & Xingzhi Song & Xizeng Mao & A. Gordon Robertson & Gabriele Roma, 2022. "Multi-modal molecular programs regulate melanoma cell state," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    4. Michael F. Emmons & Richard L. Bennett & Alberto Riva & Kanchan Gupta & Larissa Anastasio Da Costa Carvalho & Chao Zhang & Robert Macaulay & Daphne Dupéré-Richér & Bin Fang & Edward Seto & John M. Koo, 2023. "HDAC8-mediated inhibition of EP300 drives a transcriptional state that increases melanoma brain metastasis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    5. Pakavarin Louphrasitthiphol & Alessia Loffreda & Vivian Pogenberg & Sarah Picaud & Alexander Schepsky & Hans Friedrichsen & Zhiqiang Zeng & Anahita Lashgari & Benjamin Thomas & E. Elizabeth Patton & M, 2023. "Acetylation reprograms MITF target selectivity and residence time," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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