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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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Research Article Oncology Article has an altmetric score of 1

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

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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 1

Compromising PEX3 sensitizes melanoma to MAPK inhibition.

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Compromising PEX3 sensitizes melanoma to MAPK inhibition.
(A) Left: Pie ...
(A) Left: Pie chart showing percentage of patients (n = 46) with increased or decreased transcript levels of peroxisome-related genes (KEGG_Peroxisome) after treatment with MAPK-targeted therapies. Right: Normalized enrichment scores (NESs) assessing increase (positive) or decrease (negative) of KEGG_Peroxisome gene set in samples from each patient collected before versus after treatment with indicated MAPK inhibitors. (B) Top: Percentage apoptotic cells as measured by the sum of PI/Annexin V double-positive and Annexin V–positive staining. Bottom: Western blot analysis of the indicated proteins in human melanoma cells or immortalized melanocytes (MelST) following PEX3 knockdown (or siCtrl transfection) and treatment with indicated MAPK inhibitors (n = 4). Equal volumes of DMSO were added to the control groups. Detailed treatment and timeline are presented in Supplemental Table 1. Two-way ANOVA. Cl-PARP, cleaved poly(ADP-ribose) polymerase. (C) Western blot analysis of the indicated proteins (left) and relative number of ABCD3 puncta (right) in D4M.3a Cas9-Ctrl, Pex3+/– clone 6D, and Pex3+/– clone 9G cells. Representative immunofluorescent staining for ABCD3 (green) and DAPI nuclear stain (blue) are presented (n = 3). Scale bars: 10 μm. One-way ANOVA. (D) Percentage apoptosis detected in D4M.3a Cas9-Ctrl, 6D, and 9G cells following vemurafenib (vemu) or DMSO treatment for 24 hours (n = 3). Two-way ANOVA. (E) Kaplan-Meier curves showing initiation of D4M.3a Cas9-Ctrl–, 6D-, and 9G-derived melanomas. Log-rank test. (F and G) Waterfall plots showing (F) the short-term response (STR, 48-hour treatment) and (G) the best response (BR) of D4M.3a Cas9-Ctrl–, 6D-, and 9G-derived melanomas to PLX4720. Values represent percentage volume change of each tumor from baseline. One-way ANOVA. (H) Kaplan-Meier curves showing progression-free survival of mice bearing D4M.3a Cas9-Ctrl–, 6D-, and 9G-derived melanomas, fed with PLX4720 chow. Log-rank test. Data in B–D represent mean ± SD. Number of biological replicates is indicated in each graph.

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