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Cited by 130Melanoma and MAPK PathwaysCancer, Lipids, and MetabolismCancer Immunotherapy and Biomarkers

A Fatty Acid Oxidation-dependent Metabolic Shift Regulates the Adaptation of BRAF -mutated Melanoma to MAPK Inhibitors

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Aloia, Andrea, Müllhaupt, Daniela, Chabbert, Christophe D., Eberhart, Tanja, Flückiger-Mangual, Stefanie, Vukolic, Ana, Eichhoff, Ossia, Irmisch, Anja +18 more·2019·Clinical Cancer Research
DOI 10.1158/1078-0432.ccr-19-0253PMC PMC6906212

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Abstract

Purpose: Treatment of BRAFV600E-mutant melanomas with MAPK inhibitors (MAPKi) results in significant tumor regression, but acquired resistance is pervasive. To understand nonmutational mechanisms underlying the adaptation to MAPKi and to identify novel vulnerabilities of melanomas treated with MAPKi, we focused on the initial response phase during treatment with MAPKi. Experimental Design: By screening proteins expressed on the cell surface of melanoma cells, we identified the fatty acid transporter CD36 as the most consistently upregulated protein upon short-term treatment with MAPKi. We further investigated the effects of MAPKi on fatty acid metabolism using in vitro and in vivo models and analyzing patients' pre- and on-treatment tumor specimens. Results: Melanoma cells treated with MAPKi displayed increased levels of CD36 and of PPARα-mediated and carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). While CD36 is a useful marker of melanoma cells during adaptation and drug-tolerant phases, the upregulation of CD36 is not functionally involved in FAO changes that characterize MAPKi-treated cells. Increased FAO is required for BRAFV600E-mutant melanoma cells to survive under the MAPKi-induced metabolic stress prior to acquiring drug resistance. The upfront and concomitant inhibition of FAO, glycolysis, and MAPK synergistically inhibits tumor cell growth in vitro and in vivo. Conclusions: Thus, we identified a clinically relevant therapeutic approach that has the potential to improve initial responses and to delay acquired drug resistance of BRAFV600E-mutant melanoma.

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  1. [1]Balch CM, Gershenwald JE, Soong SJ, Thompson JF, Atkins MB, Byrd DR, Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol 2009; 27(36): 6199– 206 doi 10.1200/JCO.2009.23.4799. 19917835 PMC2793035 · DOI
  2. [2]Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Mutations of the BRAF gene in human cancer. Nature 2002; 417(6892): 949– 54 doi 10.1038/nature00766. 12068308 · DOI · Paper page
  3. [3]Caenepeel S, Cooke K, Wadsworth S, Huang G, Robert L, Moreno BH, MAPK pathway inhibition induces MET and GAB1 levels, priming BRAF mutant melanoma for rescue by hepatocyte growth factor. Oncotarget 2017; 8(11): 17795– 809 doi 10.18632/oncotarget.14855. 28147313 PMC5392287 · DOI
  4. [4]Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004; 5(11): 875– 85 doi 10.1038/nrm1498. 15520807 · DOI
  5. [5]Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci U S A 2008; 105(8): 3041– 6 doi 10.1073/pnas.0711741105. 18287029 PMC2268581 · DOI · Paper page
  6. [6]Gopal YN, Deng W, Woodman SE, Komurov K, Ram P, Smith PD, Basal and treatment-induced activation of AKT mediates resistance to cell death by AZD6244 (ARRY-142886) in Braf-mutant human cutaneous melanoma cells. Cancer Res 2010; 70(21): 8736– 47 doi 10.1158/0008-5472.CAN-10-0902. 20959481 PMC4286702 · DOI
  7. [8]Larkin J, Ascierto PA, Dreno B, Atkinson V, Liszkay G, Maio M, Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 2014; 371(20): 1867– 76 doi 10.1056/NEJMoa1408868. 25265494 · DOI
  8. [9]Chan MM, Haydu LE, Menzies AM, Azer MW, Klein O, Lyle M, The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition. Cancer 2014; 120(20): 3142– 53 doi 10.1002/cncr.28851. 24985732 · DOI
  9. [10]Lo RS, Shi H. Detecting mechanisms of acquired BRAF inhibitor resistance in melanoma. Methods Mol Biol 2014; 1102: 163– 74 doi 10.1007/978-1-62703-727-3_10. 24258979 · DOI
  10. [11]Shi H, Hugo W, Kong X, Hong A, Koya RC, Moriceau G, Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 2014; 4(1): 80– 93 doi 10.1158/2159-8290.CD-13-0642. 24265155 PMC3936420 · DOI · Paper page
  11. [12]Hugo W, Shi H, Sun L, Piva M, Song C, Kong X, Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance. Cell 2015; 162(6): 1271– 85 doi 10.1016/j.cell.2015.07.061. 26359985 PMC4821508 · DOI
  12. [14]Konieczkowski DJ, Johannessen CM, Abudayyeh O, Kim JW, Cooper ZA, Piris A, A melanoma cell state distinction influences sensitivity to MAPK pathway inhibitors. Cancer Discov 2014; 4(7): 816– 27 doi 10.1158/2159-8290.CD-13-0424. 24771846 PMC4154497 · DOI
  13. [15]Parmenter TJ, Kleinschmidt M, Kinross KM, Bond ST, Li J, Kaadige MR, Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov 2014; 4(4): 423– 33 doi 10.1158/2159-8290.CD-13-0440. 24469106 PMC4110245 · DOI
  14. [16]Haq R, Shoag J, Andreu-Perez P, Yokoyama S, Edelman H, Rowe GC, Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 2013; 23(3): 302– 15 doi 10.1016/j.ccr.2013.02.003. 23477830 PMC3635826 · DOI · Paper page
  15. [17]Vazquez F, Lim JH, Chim H, Bhalla K, Girnun G, Pierce K, PGC1alpha expression defines a subset of human melanoma tumors with increased mitochondrial capacity and resistance to oxidative stress. Cancer Cell 2013; 23(3): 287– 301 doi 10.1016/j.ccr.2012.11.020. 23416000 PMC3708305 · DOI · Paper page
  16. [18]Zhang G, Frederick DT, Wu L, Wei Z, Krepler C, Srinivasan S, Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. J Clin Invest 2016; 126(5): 1834– 56 doi 10.1172/JCI82661. 27043285 PMC4855947 · DOI
  17. [19]Raaijmakers MI, Widmer DS, Maudrich M, Koch T, Langer A, Flace A, A new live-cell biobank workflow efficiently recovers heterogeneous melanoma cells from native biopsies. Exp Dermatol 2015; 24(5): 377– 80 doi 10.1111/exd.12683. 25739758 · DOI
  18. [20]Liao Y, Smyth GK, Shi W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 2014; 30(7): 923– 30 doi 10.1093/bioinformatics/btt656. 24227677 · DOI · Paper page
  19. [21]Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010; 26(1): 139– 40 doi 10.1093/bioinformatics/btp616. 19910308 PMC2796818 · DOI · Paper page
  20. [22]Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25(4): 402– 8 doi 10.1006/meth.2001.1262. 11846609 · DOI · Paper page
  21. [23]Knobloch M, Pilz GA, Ghesquiere B, Kovacs WJ, Wegleiter T, Moore DL, A Fatty Acid Oxidation-Dependent Metabolic Shift Regulates Adult Neural Stem Cell Activity. Cell Rep 2017; 20(9): 2144– 55 doi 10.1016/j.celrep.2017.08.029. 28854364 PMC5583518 · DOI
  22. [24]Di Veroli GY, Fornari C, Wang D, Mollard S, Bramhall JL, Richards FM, Combenefit: an interactive platform for the analysis and visualization of drug combinations. Bioinformatics 2016; 32(18): 2866– 8 doi 10.1093/bioinformatics/btw230. 27153664 PMC5018366 · DOI
  23. [25]Kuroda H, Kutner RH, Bazan NG, Reiser J. Simplified lentivirus vector production in protein-free media using polyethylenimine-mediated transfection. J Virol Methods 2009; 157(2): 113– 21 doi 10.1016/j.jviromet.2008.11.021. 19114057 · DOI
  24. [26]Yin H, Flynn AD. Drugging Membrane Protein Interactions. Annu Rev Biomed Eng 2016; 18: 51– 76 doi 10.1146/annurev-bioeng-092115-025322. 26863923 PMC4968933 · DOI
  25. [27]Rambow F, Rogiers A, Marin-Bejar O, Aibar S, Femel J, Dewaele M, Toward Minimal Residual Disease-Directed Therapy in Melanoma. Cell 2018; 174(4): 843– 55 e19 doi 10.1016/j.cell.2018.06.025. 30017245 · DOI · Paper page
  26. [28]Pascual G, Avgustinova A, Mejetta S, Martin M, Castellanos A, Attolini CS, Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature 2017; 541(7635): 41– 5 doi 10.1038/nature20791. 27974793 · DOI
  27. [29]Glatz JFC, Luiken J. Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization. J Lipid Res 2018; 59(7): 1084– 93 doi 10.1194/jlr.R082933. 29627764 PMC6027920 · DOI
  28. [30]Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 2017; 551(7679): 247– 50 doi 10.1038/nature24297. 29088702 PMC5933935 · DOI · Paper page
  29. [31]Boiko AD, Razorenova OV, van de Rijn M, Swetter SM, Johnson DL, Ly DP, Human melanoma-initiating cells express neural crest nerve growth factor receptor CD271. Nature 2010; 466(7302): 133– 7 doi 10.1038/nature09161. 20596026 PMC2898751 · DOI
  30. [32]Ye H, Adane B, Khan N, Sullivan T, Minhajuddin M, Gasparetto M, Leukemic Stem Cells Evade Chemotherapy by Metabolic Adaptation to an Adipose Tissue Niche. Cell Stem Cell 2016; 19(1): 23– 37 doi 10.1016/j.stem.2016.06.001. 27374788 PMC4938766 · DOI
  31. [33]Banks AS, McAllister FE, Camporez JP, Zushin PJ, Jurczak MJ, Laznik-Bogoslavski D, An ERK/Cdk5 axis controls the diabetogenic actions of PPARgamma. Nature 2015; 517(7534): 391– 5 doi 10.1038/nature13887. 25409143 PMC4297557 · DOI
  32. [34]Bost F, Aouadi M, Caron L, Even P, Belmonte N, Prot M, The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes 2005; 54(2): 402– 11. 15677498
  33. [35]Zhang M, Di Martino JS, Bowman RL, Campbell NR, Baksh SC, Simon-Vermot T, Adipocyte-Derived Lipids Mediate Melanoma Progression via FATP Proteins. Cancer Discov 2018; 8(8): 1006– 25 doi 10.1158/2159-8290.CD-17-1371. 29903879 PMC6192670 · DOI
  34. [36]Houten SM, Wanders RJ. A general introduction to the biochemistry of mitochondrial fatty acid beta-oxidation. J Inherit Metab Dis 2010; 33(5): 469– 77 doi 10.1007/s10545-010-9061-2. 20195903 PMC2950079 · DOI · Paper page
  35. [37]Ibrahimi A, Sfeir Z, Magharaie H, Amri EZ, Grimaldi P, Abumrad NA. Expression of the CD36 homolog (FAT) in fibroblast cells: effects on fatty acid transport. Proc Natl Acad Sci U S A 1996; 93(7): 2646– 51. 8610095 PMC39684
  36. [38]Rozovski U, Harris DM, Li P, Liu Z, Jain P, Ferrajoli A, STAT3-activated CD36 facilitates fatty acid uptake in chronic lymphocytic leukemia cells. Oncotarget 2018; 9(30): 21268– 80 doi 10.18632/oncotarget.25066. 29765537 PMC5940394 · DOI
  37. [39]Xu S, Jay A, Brunaldi K, Huang N, Hamilton JA. CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 2013; 52(41): 7254– 61 doi 10.1021/bi400914c. 24090054 · DOI
  38. [40]Son NH, Basu D, Samovski D, Pietka TA, Peche VS, Willecke F, Endothelial cell CD36 optimizes tissue fatty acid uptake. J Clin Invest 2018; 128(10): 4329– 42 doi 10.1172/JCI99315. 30047927 PMC6159965 · DOI
  39. [41]Murray AJ, Montgomery HE, Feelisch M, Grocott MPW, Martin DS. Metabolic adjustment to high-altitude hypoxia: from genetic signals to physiological implications. Biochem Soc Trans 2018; 46(3): 599– 607 doi 10.1042/BST20170502. 29678953 · DOI
  40. [42]Nsiah-Sefaa A, McKenzie M. Combined defects in oxidative phosphorylation and fatty acid beta-oxidation in mitochondrial disease. Biosci Rep 2016; 36(2) doi 10.1042/BSR20150295. PMC4793296 26839416 · DOI
  41. [43]Camarda R, Zhou AY, Kohnz RA, Balakrishnan S, Mahieu C, Anderton B, Inhibition of fatty acid oxidation as a therapy for MYC-overexpressing triple-negative breast cancer. Nat Med 2016; 22(4): 427– 32 doi 10.1038/nm.4055. 26950360 PMC4892846 · DOI
  42. [44]Tan Z, Xiao L, Tang M, Bai F, Li J, Li L, Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy. Theranostics 2018; 8(9): 2329– 47 doi 10.7150/thno.21451. 29721083 PMC5928893 · DOI
  43. [45]Schlaepfer IR, Glode LM, Hitz CA, Pac CT, Boyle KE, Maroni P, Inhibition of Lipid Oxidation Increases Glucose Metabolism and Enhances 2-Deoxy-2-[(18)F]Fluoro-D-Glucose Uptake in Prostate Cancer Mouse Xenografts. Mol Imaging Biol 2015; 17(4): 529– 38 doi 10.1007/s11307-014-0814-4. 25561013 PMC4493937 · DOI
  44. [46]Ratnikov BI, Scott DA, Osterman AL, Smith JW, Ronai ZA. Metabolic rewiring in melanoma. Oncogene 2017; 36(2): 147– 57 doi 10.1038/onc.2016.198. 27270434 PMC5140782 · DOI
  45. [47]Li B, Li X, Ni Z, Zhang Y, Zeng Y, Yan X, Dichloroacetate and metformin synergistically suppress the growth of ovarian cancer cells. Oncotarget 2016; 7(37): 59458– 70 doi 10.18632/oncotarget.10694. 27449090 PMC5312324 · DOI
  46. [48]Marini C, Bianchi G, Buschiazzo A, Ravera S, Martella R, Bottoni G, Divergent targets of glycolysis and oxidative phosphorylation result in additive effects of metformin and starvation in colon and breast cancer. Sci Rep 2016; 6: 19569 doi 10.1038/srep19569. 26794854 PMC4726140 · DOI
  47. [50]Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, Enhancing CD8(+) T Cell Fatty Acid Catabolism within a Metabolically Challenging Tumor Microenvironment Increases the Efficacy of Melanoma Immunotherapy. Cancer Cell 2017; 32(3): 377– 91 e9 doi 10.1016/j.ccell.2017.08.004. 28898698 PMC5751418 · DOI

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Authors
Aloia, A., Müllhaupt, D., Chabbert, C. D., Eberhart, T., Flückiger-Mangual, S., Vukolic, A., Eichhoff, O., Irmisch, A., Alexander, L. T., Scibona, E., Frederick, D. T., Miao, B., Tian, T., Cheng, C., Kwong, L. N., Wei, Z., Sullivan, R. J., Boland, G. M., Herlyn, M., Flaherty, K. T., Zamboni, N., Dummer, R., Zhang, G., Levesque, M. P., Krek, W., & Kovacs, W. J.
Affiliations
  • ETH Zurich (CH)
  • University Hospital Zurich (CH)
  • Massachusetts General Hospital (US)
  • New Jersey Institute of Technology (US)
  • The University of Texas MD Anderson Cancer Center (US)
  • The Wistar Institute (US)
Corresponding author
  • Aloia, Andrea
  • Kovacs, Werner J.
ORCID
Venue
Clinical Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2019-11-15
Volume
25
Issue
22
Pages
6852-6867
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
DOI
10.1158/1078-0432.ccr-19-0253
PMC
PMC6906212
OpenAlex
W2964974081
Cited by
130
References
3
Citations by year
2026: 9 · 2025: 20 · 2024: 24 · 2023: 22 · 2022: 25 · 2021: 16 · 2020: 14
FWCI
4.55
Type
journal article
Language
en
Open access
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Repository for Publications and Research Data (ETH Zurich) (submittedVersion, other-oa)
  • Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
  • ETH Zürich Research Collection
Funders
  • Swiss National Science Foundation (31003A_166245)
  • NIH (P01 CA114046, P50 CA174523, U54 CA224070)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
MAPK inhibitors, acquired drug resistance, fatty acid oxidation, CD36, PPARα, CPT1A, metabolic stress, glycolysis, metabolic reprogramming, combination therapy, tumor cell survival
MeSH terms
Adaptation, Biological, Alleles, Animals, Disease Models, Animal, Fatty Acids, Genotype, Glycolysis, Humans, Melanoma, Models, Biological, Mutation, Neoplasm Staging, Oxidation-Reduction, Biomarkers, Gene Expression Regulation, Neoplastic, Immunophenotyping, CD36 Antigens, Drug Resistance, Neoplasm, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, PPAR alpha, Proto-Oncogene Proteins B-raf, Cell Proliferation, Mice

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