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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 7

Dual inhibition of PEX3 and UGCG overcomes MAPKi resistance in melanoma.

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Dual inhibition of PEX3 and UGCG overcomes MAPKi resistance in melanoma....
(A) Percentage apoptosis detected in MAPKi-resistant cells following PEX3 or UGCG knockdown and treatment with PPMP. Equal volumes of DMSO were added to the control groups. Cells were maintained in the presence of indicated MAPKis (Supplemental Table 1). Detailed treatment and timeline are presented in Supplemental Table 1. Data represent mean ± SD (n = 3). Two-way ANOVA. (B and D) Schematic of detailed experimental design. (C and E) Kaplan-Meier curves showing overall survival (OS) of Cas9-Ctrl or Pex3+/– clone 9G tumor–bearing mice treated with PPMP or vehicle (C) after tumors relapsed on PLX4720, or (E) after relapsed tumor reached a volume of 1,300 mm3. All mice were kept on PLX4720 chow after PLX4720 treatment was initiated when individual tumor first reached a volume of 200 mm3. Number of biological replicates (mice) is indicated in each graph. Individual tumor growth curves are shown in Supplemental Figure 7, C and D. Log-rank test.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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