Peroxisome disruption alters lipid metabolism and potentiates antitumor response with MAPK-targeted therapy in melanoma
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
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
View: Text | PDF
Research Article Oncology

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

×

Figure 4

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

Options: View larger image (or click on image) Download as PowerPoint
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.