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Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy

Author

Listed:
  • Ali Talebi

    (KU Leuven)

  • Jonas Dehairs

    (KU Leuven)

  • Florian Rambow

    (VIB Center for Cancer Biology
    KU Leuven)

  • Aljosja Rogiers

    (VIB Center for Cancer Biology
    KU Leuven)

  • David Nittner

    (VIB-KU Leuven Center for Cancer Biology
    KU Leuven)

  • Rita Derua

    (KU Leuven)

  • Frank Vanderhoydonc

    (KU Leuven)

  • Joao A. G. Duarte

    (KU Leuven
    VIB Center for Cancer Biology)

  • Francesca Bosisio

    (Department of Imaging and Pathology
    UZ Leuven)

  • Kathleen Eynde

    (Department of Imaging and Pathology
    UZ Leuven)

  • Kris Nys

    (KU Leuven)

  • Mónica Vara Pérez

    (KU Leuven)

  • Patrizia Agostinis

    (KU Leuven)

  • Etienne Waelkens

    (KU Leuven)

  • Joost Oord

    (Department of Imaging and Pathology
    UZ Leuven)

  • Sarah-Maria Fendt

    (KU Leuven
    VIB Center for Cancer Biology)

  • Jean-Christophe Marine

    (VIB Center for Cancer Biology
    KU Leuven)

  • Johannes V. Swinnen

    (KU Leuven)

Abstract

Whereas significant anti-tumor responses are observed in most BRAFV600E-mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops. Here, we show that in therapy-responsive cells BRAF inhibition induces downregulation of the processing of Sterol Regulator Element Binding (SREBP-1) and thereby lipogenesis. Irrespective of the escape mechanism, therapy-resistant cells invariably restore this process to promote lipid saturation and protect melanoma from ROS-induced damage and lipid peroxidation. Importantly, pharmacological SREBP-1 inhibition sensitizes BRAFV600E-mutant therapy-resistant melanoma to BRAFV600E inhibitors both in vitro and in a pre-clinical PDX in vivo model. Together, these data indicate that targeting SREBP-1-induced lipogenesis may offer a new avenue to overcome acquisition of resistance to BRAF-targeted therapy. This work also provides evidence that targeting vulnerabilities downstream of oncogenic signaling offers new possibilities in overcoming resistance to targeted therapies.

Suggested Citation

  • Ali Talebi & Jonas Dehairs & Florian Rambow & Aljosja Rogiers & David Nittner & Rita Derua & Frank Vanderhoydonc & Joao A. G. Duarte & Francesca Bosisio & Kathleen Eynde & Kris Nys & Mónica Vara Pérez, 2018. "Sustained SREBP-1-dependent lipogenesis as a key mediator of resistance to BRAF-targeted therapy," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04664-0
    DOI: 10.1038/s41467-018-04664-0
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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.
    2. Vincent de Laat & Halit Topal & Xander Spotbeen & Ali Talebi & Jonas Dehairs & Jakub Idkowiak & Frank Vanderhoydonc & Tessa Ostyn & Peihua Zhao & Maarten Jacquemyn & Michele Wölk & Anna Sablina & Koen, 2024. "Intrinsic temperature increase drives lipid metabolism towards ferroptosis evasion and chemotherapy resistance in pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    3. Tom Nyen & Mélanie Planque & Lilian Wagensveld & Joao A. G. Duarte & Esther A. Zaal & Ali Talebi & Matteo Rossi & Pierre-René Körner & Lara Rizzotto & Stijn Moens & Wout Wispelaere & Regina E. M. Baid, 2022. "Serine metabolism remodeling after platinum-based chemotherapy identifies vulnerabilities in a subgroup of resistant ovarian cancers," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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