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

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, Patrizia Agostinis, Etienne Waelkens, Joost Oord, Sarah-Maria Fendt, Jean-Christophe Marine and Johannes V. Swinnen ()
Additional contact information
Ali Talebi: KU Leuven
Jonas Dehairs: KU Leuven
Florian Rambow: VIB Center for Cancer Biology
Aljosja Rogiers: VIB Center for Cancer Biology
David Nittner: VIB-KU Leuven Center for Cancer Biology
Rita Derua: KU Leuven
Frank Vanderhoydonc: KU Leuven
Joao A. G. Duarte: KU Leuven
Francesca Bosisio: Department of Imaging and Pathology
Kathleen Eynde: Department of Imaging and Pathology
Kris Nys: KU Leuven
Mónica Vara Pérez: KU Leuven
Patrizia Agostinis: KU Leuven
Etienne Waelkens: KU Leuven
Joost Oord: Department of Imaging and Pathology
Sarah-Maria Fendt: KU Leuven
Jean-Christophe Marine: VIB Center for Cancer Biology
Johannes V. Swinnen: KU Leuven

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04664-0

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