Author:

Keywords:

Animals Antineoplastic Agents Cell Line, Tumor Down-Regulation Drug Resistance, Neoplasm Female Gene Expression Regulation, Neoplastic Gene Knockout Techniques Humans Lipogenesis Male Melanocytes Melanoma Mice Mice, Nude Mice, SCID Mutation Protein Kinase Inhibitors Proto-Oncogene Proteins B-raf Pyridines Signal Transduction Sterol Regulatory Element Binding Protein 1 Thiazoles Vemurafenib Xenograft Model Antitumor Assays, Science & Technology, Multidisciplinary Sciences, Science & Technology - Other Topics, FATTY-ACID SYNTHASE, ELEMENT-BINDING PROTEINS, PROSTATE-CANCER, GENE-EXPRESSION, SMALL-MOLECULE, CELLS, MELANOMA, ACTIVATION, SREBP, RAF, Animals, Antineoplastic Agents, Cell Line, Tumor, Down-Regulation, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Lipogenesis, Male, Melanocytes, Melanoma, Mice, Mice, Nude, Mice, SCID, Mutation, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Pyridines, Signal Transduction, Sterol Regulatory Element Binding Protein 1, Thiazoles, Vemurafenib, Xenograft Model Antitumor Assays, BRAF, melanoma, lipids

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.