Journal Article

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

Talebi, Ali, Derua, Rita, Fendt, Sarah-Maria, Van den Eynde, Kathleen, Waelkens, Etienne, Duarte, Joao A. G., Rogiers, Aljosja, Rambow, Florian, Bosisio, Francesca, Dehairs, Jonas, Van den Oord, Joost, Swinnen, Johannes V., Pérez, Mónica Vara, Vanderhoydonc, Frank, Marine, Jean-Christophe, Agostinis, Patrizia, Nys, Kris, Nittner, David

2018

Overview

Whereas significant anti-tumor responses are observed in most BRAF V600E -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 BRAF V600E -mutant therapy-resistant melanoma to BRAF V600E 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. Melanoma patients harbouring BRAF V600E mutation generally develop resistance to targeted therapy. In this study, the authors demonstrate that SREBP-1-mediated induction of lipid biosynthesis contributes to therapy resistance in BRAF mutant melanoma.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 14/19 / 14/63 / 140/58 / 631/45/287/1194 / 631/67/1059/2326 / 631/67/1813/1634 / 631/67/2327 / 64/60 / Animals / Antineoplastic Agents - pharmacology / Antineoplastic Agents - therapeutic use / Cell Line, Tumor / Down-Regulation / Drug Resistance, Neoplasm - genetics / Female / Gene Expression Regulation, Neoplastic - drug effects / Gene Knockout Techniques / Humanities and Social Sciences / Humans / Lipid peroxidation / Lipogenesis / Lipogenesis - drug effects / Lipogenesis - genetics / Male / MAP kinase / Melanocytes / Melanoma / Melanoma - drug therapy / Melanoma - genetics / Mice / Mice, Nude / Mice, SCID / multidisciplinary / Mutation / Peroxidation / Pharmacology / Protein Kinase Inhibitors - pharmacology / Protein Kinase Inhibitors - therapeutic use / Proto-Oncogene Proteins B-raf - antagonists & inhibitors / Proto-Oncogene Proteins B-raf - genetics / Pyridines - pharmacology / Science / Science (multidisciplinary) / Signal Transduction - genetics / Sterol Regulatory Element Binding Protein 1 - antagonists & inhibitors / Sterol Regulatory Element Binding Protein 1 - genetics / Sterol Regulatory Element Binding Protein 1 - metabolism / Sterol regulatory element-binding protein / Therapy / Thiazoles - pharmacology / Vemurafenib / Xenograft Model Antitumor Assays