Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma
Fan Huang, … , Wilson H. Miller Jr., Sonia V. del Rincón
Fan Huang, … , Wilson H. Miller Jr., Sonia V. del Rincón
Published August 24, 2023
Citation Information: J Clin Invest. 2023;133(20):e166644. https://doi.org/10.1172/JCI166644.
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Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma

Abstract

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+ 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 PEX3-PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment.

Authors

Fan Huang, Feiyang Cai, Michael S. Dahabieh, Kshemaka Gunawardena, Ali Talebi, Jonas Dehairs, Farah El-Turk, Jae Yeon Park, Mengqi Li, Christophe Goncalves, Natascha Gagnon, Jie Su, Judith H. LaPierre, Perrine Gaub, Jean-Sébastien Joyal, John J. Mitchell, Johannes V. Swinnen, Wilson H. Miller Jr., Sonia V. del Rincón

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Figure 5

Peroxisomes and UGCG are required for survival of CD36+ MAPKi-tolerant melanoma cells.

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Peroxisomes and UGCG are required for survival of CD36+ MAPKi-tolerant m...
(A) Schematic of experimental design for (B–E). A375M cells were treated with vemu (2.5 μM) for 48 hours before CD36 staining and subsequent sorting. (B) Fold change in the indicated mRNAs in vemu-exposed CD36+ A375M cells relative to CD36– A375M cells, normalized to RPLP0 as a reference gene (n = 4). The SCP2 primers amplify the N-terminus of the transcript initiated from the proximal promoter, encoding the peroxisome-specific protein SCPx. (C) Number of ABCD3 puncta and (D) relative UGCG expression in vemu-exposed CD36+ versus CD36– A375M cells. Representative immunofluorescent staining for (C) CD36 (red), ABCD3 (green), and DAPI (blue) or (D) CD36 (red), UGCG (green), and DAPI (blue) are presented. Red arrows highlight cells stained positive for CD36. (E) Percentage apoptosis (left) and representative images (right) of vemu-exposed CD36+ versus CD36– A375M cells following PEX3 knockdown and/or PPMP treatment (n = 5). Scale bars: 10 μm (C), 20 μm (D), and 50 μm (E). (F–H) Percentage of CD36+ populations in (F) A375M cells following PEX3 knockdown and the indicated treatment (n = 3), (G) A375M-Ctrl versus PEX3-KO AG3 cells upon indicated treatment (n = 3), or (H) A375M-Ctrl versus PEX3-KO AG3 cells following UGCG knockdown and subsequently treated with vemu (n = 4). Significance assessed by 2-sided unpaired t test (B–D) or 2-way ANOVA (E–H). Data represent mean ± SD.