Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma

• Published in: The Journal of clinical investigation Vol. 133; no. 20; pp. 1 - 19
• Main Authors: Huang, Fan, Cai, Feiyang, Dahabieh, Michael S., Gunawardena, Kshemaka, Talebi, Ali, Dehairs, Jonas, El-Turk, Farah, Park, Jae Yeon, Li, Mengqi, Goncalves, Christophe, Gagnon, Natascha, Su, Jie, LaPierre, Judith H., Gaub, Perrine, Joyal, Jean-Sébastien, Mitchell, John J., Swinnen, Johannes V., Miller, Wilson H., del Rincón, Sonia V.
• Format: Journal Article
• Language: English
• Published: Ann Arbor American Society for Clinical Investigation 15.10.2023
• Subjects: Antitumor activity; Apoptosis; Biomedical research; Biosynthesis; Cancer; Cancer therapies; Care and treatment; CD36 antigen; Cells; Cellulose; Ceramide; Ceramides; Cloning; Development and progression; Drug therapy; Fatty acids; Genes; Glycosyltransferase; Health aspects; Lipid metabolism; Lipids; MAP kinase; Melanoma; Metabolism; Mitogen-activated protein kinases; Mutation; Oncology; Oxidation; Patients; Peroxisomes; Physiological aspects; Skin cancer; Tumors; Vemurafenib; Canada; Quebec
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI166644

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant [CD36.sup.+] melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.