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.
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 8

NNC 55-0396 disrupts PEX3-PEX19 interaction and cooperates with PPMP to sensitize melanoma to BRAF inhibition.

Options: View larger image (or click on image) Download as PowerPoint
NNC 55-0396 disrupts PEX3-PEX19 interaction and cooperates with PPMP to ...
(A) Western blot analysis of PEX3 and PEX19 from Myc co-immunoprecipitation (co-IP) of HEK-293T cells cotransfected with GFP-PEX3– and Myc-PEX19–expressing plasmids, treated with DMSO or NNC 55-0396 (NNC, 4 μM, 24 hours). Left portion displays Myc co-IP of HEK-293T cells transfected with empty vector (EV), Myc-PEX19–, or GFP-PEX3–expressing plasmid alone. Immunoblots for inputs (10% of protein from IP) are shown below (representative of n = 3). (B) Percentage apoptosis or (C) percentage of CD36+ populations detected among A375M-Ctrl cells (left) or PEX3-KO AG3 cells (right) following indicated treatment with NNC (4 μM), vemu, and/or PPMP. (D) Percentage apoptosis detected in vemu-exposed CD36+ versus CD36– A375M cells following NNC and/or PPMP treatment (n = 3). Data in B–D represent mean ± SD. (E) Colony formation assays of a panel of MAPKi-resistant melanoma cells cultured in the presence of indicated MAPKis and treated with NNC and/or PPMP for 5 days (representative of n = 3). (F and G) Waterfall plots showing (F) the STR and (G) the BR of A375M-derived melanomas to PLX4720 alone or in combination with NNC, PPMP, or NNC+PPMP. Values represent percentage volume change of each tumor from baseline. (H) Kaplan-Meier curves showing PFS of mice bearing A375M-derived melanomas, fed with PLX4720 chow and simultaneously treated with vehicle, NNC, PPMP, or NNC+PPMP. See detailed experimental design in Supplemental Figure 9A. (I) Kaplan-Meier curves showing OS of A375M tumor–bearing mice treated with vehicle, NNC, PPMP, or NNC+PPMP after relapsed (PLX4720-resistant) tumor reached a volume of 400 mm3. Detailed experimental design and individual tumor growth curves are shown in Supplemental Figure 9, C and D, respectively. In F–I, the number of biological replicates (mice) is indicated in each graph. All mice were kept on PLX4720 chow when individual tumor first reached a volume of 200 mm3. Significance assessed by 2-way ANOVA (B–D, F, and G) or log-rank test (H and I).