Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Novel treatment strategy for NRAS-mutated melanoma through a selective inhibitor of CD147/VEGFR-2 interaction

Oncogene volume 41, pages 2254–2264 (2022)Cite this article

Subjects

Abstract

More than 70% of human NRASmut melanomas are resistant to MEK inhibitors highlighting the crucial need for efficient therapeutic strategies for these tumors. CD147, a membrane receptor, is overexpressed in most cancers including melanoma and is associated with poor prognosis. We show here that CD147i, a specific inhibitor of CD147/VEGFR-2 interaction represents a potential therapeutic strategy for NRASmut melanoma cells. It significantly inhibited the malignant properties of NRASmut melanomas ex vivo and in vivo. Importantly, NRASmut patient’s-derived xenografts, which were resistant to MEKi, became sensitive when combined with CD147i leading to decreased proliferation ex vivo and tumor regression in vivo. Mechanistic studies revealed that CD147i effects were mediated through STAT3 pathway. These data bring a proof of concept on the impact of the inhibition of CD147/VEGFR-2 interaction on melanoma progression and represents a new therapeutic opportunity for NRASmut melanoma when combined with MEKi.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Predicted 3D structures of CD147i.
Fig. 2: CD147i modulates malignant properties of melanoma cells.
Fig. 3: CD147i disrupts CD147/VEGFR-2 interaction.
Fig. 4: Specific effect of CD147i for CD147/VEGFR-2 interaction on NRASmut cells.
Fig. 5: CD147i effect is mediated through STAT3 signaling pathway.
Fig. 6: CD147i reduces undefined in vivo tumor growth of BLM and C8161 xenografts through STAT3 pathway.
Fig. 7: Combination of CD147i and MEKi reduced tumor growth of NRASmut melanoma PDX resistant to MEKi.

Similar content being viewed by others

References

  1. Davis EJ, Johnson DB, Sosman JA, Chandra S. Melanoma: what do all the mutations mean? Cancer. 2018;124:3490–9.

    Article  PubMed  Google Scholar 

  2. Chapman PB, Robert C, Larkin J, Haanen JB, Ribas A, Hogg D, et al. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol. 2017;28:2581–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hauschild A, Grob J-J, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012;380:358–65.

    Article  CAS  PubMed  Google Scholar 

  4. Delord J-P, Robert C, Nyakas M, McArthur GA, Kudchakar R, Mahipal A, et al. Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clin Cancer Res. 2017;23:5339–48.

    Article  CAS  PubMed  Google Scholar 

  5. Trojaniello C, Festino L, Vanella V, Ascierto PA. Encorafenib in combination with binimetinib for unresectable or metastatic melanoma with BRAF mutations. Expert Rev Clin Pharm. 2019;12:259–66.

    Article  CAS  Google Scholar 

  6. Long GV, Hauschild A, Santinami M, Atkinson V, Mandalà M, Chiarion-Sileni V, et al. Adjuvant Dabrafenib plus Trametinib in stage III BRAF-mutated melanoma. N Engl J Med. 2017;377:1813–23.

    Article  CAS  PubMed  Google Scholar 

  7. Larkin J, Ascierto PA, Dréno B, Atkinson V, Liszkay G, Maio M, et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med. 2014;371:1867–76.

    Article  PubMed  CAS  Google Scholar 

  8. Muñoz-Couselo E, Adelantado EZ, Ortiz C, García JS, Perez-Garcia J. NRAS-mutant melanoma: current challenges and future prospect. OncoTargets Ther. 2017;10:3941–7.

    Article  Google Scholar 

  9. Ascierto PA, Schadendorf D, Berking C, Agarwala SS, van Herpen CM, Queirolo P, et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013;14:249–56.

    Article  CAS  PubMed  Google Scholar 

  10. Hayes TK, Luo F, Cohen O, Goodale AB, Lee Y, Pantel S, et al. A functional landscape of resistance to MEK1/2 and CDK4/6 inhibition in NRAS-mutant melanoma. Cancer Res. 2019;79:2352–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Fedorenko IV, Gibney GT, Smalley KSM. NRAS mutant melanoma: biological behavior and future strategies for therapeutic management. Oncogene. 2013;32:3009–18.

    Article  CAS  PubMed  Google Scholar 

  12. Abel EV, Basile KJ, Kugel CH, Witkiewicz AK, Le K, Amaravadi RK, et al. Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J Clin Invest. 2013;123:2155–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ebi H, Corcoran RB, Singh A, Chen Z, Song Y, Lifshits E, et al. Receptor tyrosine kinases exert dominant control over PI3K signaling in human KRAS mutant colorectal cancers. J Clin Invest. 2011;121:4311–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Robinson JP, Rebecca VW, Kircher DA, Silvis MR, Smalley I, Gibney GT, et al. Resistance mechanisms to genetic suppression of mutant NRAS in melanoma. Melanoma Res. 2017;27:545–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Graells J, Vinyals A, Figueras A, Llorens A, Moreno A, Marcoval J, et al. Overproduction of VEGF concomitantly expressed with its receptors promotes growth and survival of melanoma cells through MAPK and PI3K signaling. J Invest Dermatol. 2004;123:1151–61.

    Article  CAS  PubMed  Google Scholar 

  16. Oladipupo SS, Kabir AU, Smith C, Choi K, Ornitz DM. Impaired tumor growth and angiogenesis in mice heterozygous for Vegfr2 (Flk1). Sci Rep. 2018. https://doi.org/10.1038/s41598-018-33037-2.

  17. Khayati F, Pérez-Cano L, Maouche K, Sadoux A, Boutalbi Z, Podgorniak MP, et al. EMMPRIN/CD147 is a novel coreceptor of VEGFR-2 mediating its activation by VEGF. Oncotarget. 2015;6:9766–80.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Caudron A, Battistella M, Feugeas J-P, Pages C, Basset-Seguin N, Mazouz Dorval S, et al. EMMPRIN/CD147 is an independent prognostic biomarker in cutaneous melanoma. Exp Dermatol. 2016;25:618–22.

    Article  CAS  PubMed  Google Scholar 

  19. Tang Y, Nakada MT, Kesavan P, McCabe F, Millar H, Rafferty P, et al. Extracellular matrix metalloproteinase inducer stimulates tumor angiogenesis by elevating vascular endothelial cell growth factor and matrix metalloproteinases. Cancer Res. 2005;65:3193–9.

    Article  CAS  PubMed  Google Scholar 

  20. Landras A, Reger de Moura C, Jouenne F, Lebbe C, Menashi S, Mourah S. CD147 is a promising target of tumor progression and a prognostic biomarker. Cancers. 2019. https://doi.org/10.3390/cancers11111803.

  21. Grass GD, Tolliver LB, Bratoeva M, Toole BP. CD147, CD44, and the epidermal growth factor receptor (EGFR) signaling pathway cooperate to regulate breast epithelial cell invasiveness. J Biol Chem. 2013;288:26089–104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Foster SA, Whalen DM, Özen A, Wongchenko MJ, Yin J, Yen I, et al. Activation mechanism of oncogenic deletion mutations in BRAF, EGFR, and HER2. Cancer Cell. 2016;29:477–93.

    Article  CAS  PubMed  Google Scholar 

  23. Hillion J, Dhara S, Sumter TF, Mukherjee M, Di Cello F, Belton A, et al. The high-mobility group A1a/signal transducer and activator of transcription-3 axis: an achilles heel for hematopoietic malignancies? Cancer Res. 2008;68:10121–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Carpenter RL, Lo H-W. STAT3 target genes relevant to human cancers. Cancers. 2014;6:897–925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Delyon J, Varna M, Feugeas J-P, Sadoux A, Yahiaoui S, Podgorniak MP, et al. Validation of a preclinical model for assessment of drug efficacy in melanoma. Oncotarget. 2016;7:13069–81.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Delyon J, Chevret S, Jouary T, Dalac S, Dalle S, Guillot B, et al. STAT3 mediates nilotinib response in KIT-altered melanoma: a phase II multicenter trial of the french skin cancer network. J Invest Dermatol. 2018;138:58–67.

    Article  CAS  PubMed  Google Scholar 

  27. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14:736–46.

    Article  CAS  PubMed  Google Scholar 

  28. Chen S-H, Murphy DA, Lassoued W, Thurston G, Feldman MD, Lee WMF. Activated STAT3 is a mediator and biomarker of VEGF endothelial activation. Cancer Biol Ther. 2008;7:1994–2003.

    Article  CAS  PubMed  Google Scholar 

  29. Kim J, Novak D, Sachpekidis C, Utikal J, Larribère L. STAT3 relays a differential response to melanoma-associated NRAS mutations. Cancers. 2020;12:119.

    Article  PubMed Central  CAS  Google Scholar 

  30. Fu ZG, Wang L, Cui HY, Peng JL, Wang SJ, Geng JJ, et al. A novel small-molecule compound targeting CD147 inhibits the motility and invasion of hepatocellular carcinoma cells. Oncotarget. 2016;7:9429–47.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Wu P-K, Park J-I. MEK1/2 inhibitors: molecular activity and resistance mechanisms. Semin Oncol. 2015;42:849–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mahapatra DK, Asati V, Bharti SK. MEK inhibitors in oncology: a patent review (2015-Present). Expert Opin Ther Pat. 2017;27:887–906.

    Article  CAS  PubMed  Google Scholar 

  33. Mandalà M, Merelli B, Massi D. Nras in melanoma: targeting the undruggable target. Crit Rev Oncol Hematol. 2014;92:107–22.

    Article  PubMed  Google Scholar 

  34. Sarkisian S, Davar D. MEK inhibitors for the treatment of NRAS mutant melanoma. Drug Des Devel Ther. 2018;12:2553–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Boespflug A, Caramel J, Dalle S, Thomas L. Treatment of NRAS-mutated advanced or metastatic melanoma: rationale, current trials and evidence to date. Ther Adv Med Oncol. 2017;9:481–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lebbé C, Dutriaux C, Lesimple T, Kruit W, Kerger J, Thomas L, et al. Pimasertib versus dacarbazine in patients with unresectable NRAS-mutated cutaneous melanoma: phase II, randomized, controlled trial with crossover. Cancers. 2020. https://doi.org/10.3390/cancers12071727.

  37. Dummer R, Schadendorf D, Ascierto PA, Arance A, Dutriaux C, Di Giacomo AM, et al. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:435–45.

    Article  CAS  PubMed  Google Scholar 

  38. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature. 2010;468:973–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sun C, Bernards R. Feedback and redundancy in receptor tyrosine kinase signaling: relevance to cancer therapies. Trends Biochem Sci. 2014;39:465–74.

    Article  CAS  PubMed  Google Scholar 

  40. Echevarría‐Vargas IM, Reyes‐Uribe PI, Guterres AN, Yin X, Kossenkov AV, Liu Q, et al. Co‐targeting BET and MEK as salvage therapy for MAPK and checkpoint inhibitor‐resistant melanoma. EMBO Mol Med. 2018. https://doi.org/10.15252/emmm.201708446.

  41. Posch C, Moslehi H, Feeney L, Green GA, Ebaee A, Feichtenschlager V, et al. Combined targeting of MEK and PI3K/mTOR effector pathways is necessary to effectively inhibit NRAS mutant melanoma in vitro and in vivo. Proc Natl Acad Sci USA. 2013;110:4015–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Kinsey CG, Camolotto SA, Boespflug AM, Guillen KP, Foth M, Truong A, et al. Protective autophagy elicited by RAF→MEK→ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med. 2019;25:620–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Eisen T, Ahmad T, Flaherty KT, Gore M, Kaye S, Marais R, et al. Sorafenib in advanced melanoma: a phase II randomised discontinuation trial analysis. Br J Cancer. 2006;95:581–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Decoster L, Vande Broek I, Neyns B, Majois F, Baurain JF, Rottey S, et al. Biomarker analysis in a phase II study of sunitinib in patients with advanced melanoma. Anticancer Res. 2015;35:6893–9.

    CAS  PubMed  Google Scholar 

  45. Ivy SP, Wick JY, Kaufman BM. An overview of small-molecule inhibitors of VEGFR signaling. Nat Rev Clin Oncol. 2009;6:569–79.

    Article  CAS  PubMed  Google Scholar 

  46. Jiang T, Zhuang J, Duan H, Luo Y, Zeng Q, Fan K, et al. CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood. 2012;120:2330–9.

    Article  CAS  PubMed  Google Scholar 

  47. Jouve N, Bachelier R, Despoix N, Blin MG, Matinzadeh MK, Poitevin S, et al. CD146 mediates VEGF-induced melanoma cell extravasation through FAK activation. Int J Cancer. 2015;137:50–60.

    Article  CAS  PubMed  Google Scholar 

  48. Whitaker GB, Limberg BJ, Rosenbaum JS. Vascular endothelial growth factor receptor-2 and neuropilin-1 form a receptor complex that is responsible for the differential signaling potency of VEGF165 and VEGF121. J Biol Chem. 2001;276:25520–31.

    Article  CAS  PubMed  Google Scholar 

  49. Favier B, Alam A, Barron P, Bonnin J, Laboudie P, Fons P, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood. 2006;108:1243–50.

    Article  CAS  PubMed  Google Scholar 

  50. Tremmel M, Matzke A, Albrecht I, Laib AM, Olaku V, Ballmer-Hofer K, et al. A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis. Blood. 2009;114:5236–44.

    Article  CAS  PubMed  Google Scholar 

  51. Koch S, Claesson-Welsh L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med. 2012. https://doi.org/10.1101/cshperspect.a006502.

  52. Bougatef F, Quemener C, Kellouche S, Naïmi B, Podgorniak MP, Millot G, et al. EMMPRIN promotes angiogenesis through hypoxia-inducible factor-2 -mediated regulation of soluble VEGF isoforms and their receptor VEGFR-2. Blood. 2009;114:5547–56.

    Article  CAS  PubMed  Google Scholar 

  53. Lockshin A, Giovanella BC, De Ipolyi PD, Williams LJ, Mendoza JT, Yim SO, et al. Exceptional lethality for nude mice of cells derived from a primary human melanoma. Cancer Res. 1985;45:345–50.

    CAS  PubMed  Google Scholar 

  54. Reger de Moura C, Vercellino L, Jouenne F, Baroudjian B, Sadoux A, Louveau B, et al. Intermittent versus continuous dosing of MAPK inhibitors in the treatment of BRAF-mutated melanoma. Transl Oncol. 2019;13:275–86.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by La Ligue Nationale contre le Cancer, the Institut National de la Santé et de la Recherche Médicale (INSERM) and La Société Française de Dermatologie. AL was supported by a PhD funding from La Ligue Nationale contre le Cancer and the Spanish Ministry of Science and Innovation (PID2019-110167RB-I00). We thank technological platform of the Institut Recherche Saint-Louis (IRSL) for confocal microscopy analyses and Dr Benoit Souquet for technical support.

Author information

Author notes

  1. These authors contributed equally: Alexandra Landras, Coralie Reger De Moura.

Authors and Affiliations

  1. Inserm, UMR_S976, Université de Paris, F-75010, Paris, France

    Alexandra Landras, Coralie Reger de Moura, Maxime Battistella, Nicolas Dumaz, Céleste Lebbé & Samia Mourah

  2. Pharmacogenomics Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France

    Coralie Reger de Moura, Aurélie Sadoux, Suzanne Menashi & Samia Mourah

  3. Inserm, UMR_S1141, Hopital Robert Debré, F-75019, Paris, France

    Bruno O. Villoutreix

  4. Pathology Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France

    Maxime Battistella

  5. Instituto de Ciencias de la Vid y del Vino (ICVV), CSIC—Universidad de La Rioja—Gobierno de La Rioja, Logroño, Spain

    Juan Fernández-Recio

  6. Dermatology Department, Hopital Saint Louis, AP-HP, F-75010, Paris, France

    Céleste Lebbé

Authors
  1. Alexandra Landras
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Coralie Reger de Moura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bruno O. Villoutreix
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Maxime Battistella
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aurélie Sadoux
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nicolas Dumaz
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Suzanne Menashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Juan Fernández-Recio
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Céleste Lebbé
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Samia Mourah
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SMo designed and supervised the study. SMe and CL contributed to the design. AL and CRdM performed and analyzed in vitro, ex vivo and in vivo experiments. BOV and JFR performed and analyzed in silico data. AS performed genomic analyses. ND provided reagents, technical and scientific expertise. MB performed tissue specimen analysis. CL provided materials scientific and clinical expertise. AL wrote the manuscript with input from all co-authors.

Corresponding author

Correspondence to Samia Mourah.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Landras, A., Reger de Moura, C., Villoutreix, B.O. et al. Novel treatment strategy for NRAS-mutated melanoma through a selective inhibitor of CD147/VEGFR-2 interaction. Oncogene 41, 2254–2264 (2022). https://doi.org/10.1038/s41388-022-02244-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-022-02244-7

Search

Advanced search

Quick links