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.
Highlights
Whereas significant anti-tumor responses are observed in most BRAFV600E-mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops
We show that the lipogenic pathway is a key mediator of oncogenic BRAF and that its constitutive activation, which is mediated by SREBP-1, contributes to therapy resistance
Alterations in the expression of these enzymes by mutant BRAF inhibition was confirmed by RT-qPCR on an extended panel of therapy-sensitive BRAFV600E parental and isogenic cell lines that have acquired resistance to vemurafenib through diverse mechanisms (Supplementary Table 1)
Summary
Whereas significant anti-tumor responses are observed in most BRAFV600E-mutant melanoma patients exposed to MAPK-targeting agents, resistance almost invariably develops. While targeted approaches are revolutionizing the treatment of cancer, the management of both intrinsic and acquired therapy resistance remains a major limitation This is exemplified by the unprecedented, but transient, anti-tumor responses seen in patients with BRAFV600Emutant malignant melanoma exposed to agents that selectively inhibit oncogenic BRAF1,2. Different mutational events can be selected in distinct drug-resistant clones from the same patient[9] and even co-occur within the same lesion[10] These findings have highlighted the need to improve effectiveness of treatment, by for instance, the co-targeting of other essential cancer vulnerabilities and/or key mediators of MAPK signaling itself. Our findings support the use of SREBP-1 inhibitors in a novel combinatorial approach to overcome resistance to BRAFV600E-targeted therapy
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