Metastatic melanoma is the most aggressive and obstinate skin cancer with poor prognosis.,Variant novel applicable regimens have emerged during the past decades intensively, while the most profound approaches are oncogene-targeted therapy and T-lymphocyte mediated immunotherapy.,Although targeted therapies generated remarkable and rapid clinical responses in the majority of patients, acquired resistance was developed promptly within months leading to tumor relapse.,By contrast, immunotherapies elicited long-term tumor regression.,However, the overall response rate was limited.,In view of the above, either targeted therapy or immunotherapy cannot elicit durable clinical responses in large range of patients.,Interestingly, the advantages and limitations of these regimens happened to be complementary.,An increasing number of preclinical studies and clinical trials proved a synergistic antitumor effect with the combination of targeted therapy and immunotherapy, implying a promising prospect for the treatment of metastatic melanoma.,In order to achieve a better therapeutic effectiveness and reduce toxicity in patients, great efforts need to be made to illuminate multifaceted interplay between targeted therapy and immunotherapy.
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.,Melanoma patients harbouring BRAFV600E 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.