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 6

Increased peroxisomal and UGCG activity commonly occurs in melanomas that rapidly acquire resistance to MAPK-targeted therapy.

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Increased peroxisomal and UGCG activity commonly occurs in melanomas tha...
(A) Normalized gene expression of CD36 (left), relative expression of a peroxisomal gene signature (right), and (B) expression of AGPS, SCP2, PEX1, and UGCG in a cohort of melanoma samples (n = 17 out of a total of 22 patients, Kwong 2015 data set) collected before, while on, or relapsed on MAPK-targeted therapy showing an overall trend of CD36 induction upon MAPKi. Data represent mean + SEM. One-way ANOVA. (C and D) Normalized abundance of indicated lipid species grouped by carbon chain length detected in (C) MEL006 PDX tumor samples collected before (Pre, n = 6) or relapsed (Res, n = 5) on dabrafenib+trametinib treatment, or (D) 451Lu parental (Par) cells versus vemu-resistant 451Lu-R cells (n = 3). Two-way ANOVA. PE-O, 1-alkyl,2-acylphosphatidylethanolamine; PC-O, 1-alkyl,2-acylphosphatidylcholine. (E) Fold change in AGPS and UGCG mRNA levels in a panel of MAPKi-resistant melanoma cells relative to their corresponding parental cells, normalized to ACTB as a reference gene (n = 4). Data in C–E represent mean ± SD. (F) Western blot analysis of the indicated proteins in a panel of parental versus MAPKi-resistant melanoma cells. (G) Waterfall plots showing the best overall response and (H) Kaplan-Meier curves showing PFS of melanoma patients treated with MAPK-targeted therapy. Risk score ranging between 0 and 3 was calculated based on expression of CD36, AGPS, and UGCG before and after treatment (see Supplemental Table 5 for detailed information). Patients were subsequently grouped into high-risk (risk score ≥2) versus low-risk (risk score ≤1). Values in G represent percentage response of individual patient from baseline. Significance assessed by 2-sided unpaired t test (E and G) or log-rank test (H).