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
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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

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Figure 8

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

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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).