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 4

CD36+ MAPKi-tolerant melanoma cells have retained peroxisome levels and UGCG.

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CD36+ MAPKi-tolerant melanoma cells have retained peroxisome levels and ...
(A) Heatmap showing relative expression of indicated melanoma cell-state-specific markers, a panel of peroxisomal genes, and PPARGC1A in 4 drug-tolerant melanoma populations in the MEL006 PDX model during early dabrafenib+trametinib treatment (day 4). (B) Expression of CD36 and a peroxisomal gene signature, UGCG, GBA, and PPARGC1A (HTSeq-FPKM) in the GDC TCGA Melanoma data set (SKCM, n = 472). Spearman’s rank-order. (C and D) Violin plots of scRNA-seq data highlighting the distribution of (C) a gene signature indicating cancer cell metabolic activity and (D) indicated peroxisomal genes and UGCG in CD36– (<2.2) versus CD36+ (≥2.2) cells, before or after dabrafenib+trametinib treatment for 28 days (MRD). (E) Schematic of experimental design for panels F and G. (F) Relative expression of AGPS (left) and UGCG (right) in CD36– and CD36+ cell populations isolated from A375M melanoma xenografts following vehicle (n = 4) or PLX4720+cobi (n = 7) treatment for 8 days. (G) Fold change in AGPS (left) and UGCG (right) transcripts in CD36+ cells relative to CD36– cells isolated from A375M melanoma xenografts following PLX4720+cobi treatment for 8 days. RPLP0 was used as a reference gene. Cells from a total n = 7 tumors were pooled before sorting. Two-sided unpaired t test. (H) Schematic of experimental design for I. (I) Relative expression of AGPS (left) and UGCG (right) in CD36– versus CD36+ A375M cells following treatment with DMSO, vemu (2.5 μM), or vemu (2.5 μM) combined with cobi (100 nM) for 96 hours. Significance assessed with 2-way ANOVA (C, D, F, and I). Data in F–I represent mean ± SD.