Skip to main content
SpringerLink
Log in

The CSPG4-specific monoclonal antibody enhances and prolongs the effects of the BRAF inhibitor in melanoma cells

  • UNIVERSITY OF PITTSBURGH IMMUNOLOGY 2011
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

PLX4032 is a BRAF-selective inhibitor shown to be efficacious in the treatment of melanomas presenting with the BRAFV600E mutation. However, favorable responses to treatment are short-lived, and complete remission is rarely observed. Therefore, it is important to identify novel therapies designed to enhance treatment responses and to increase the longevity of initial response to BRAF inhibitors. To this end, we characterized the effects of the 225.28 chondroitin sulfate proteoglycan 4 (CSPG4)–specific monoclonal antibody (mAb) capable of blocking multiple signaling pathways important to cell growth, migration, and survival. Addition of 225.28 to the treatment regimen enhanced the in vitro response magnitude and the duration efficacy of PLX4032 in treating CSPG4+, BRAFV600E melanoma cells (melanomaBRAF(V600E)/CSPG4+ cells). Data presented in this report demonstrated that (1) treatments comprised of PLX4032 and mAb 225.28 were more effective at inhibiting melanomaBRAF(V600E)/CSPG4+ cell growth than either agent alone, (2) mAb 225.28 prevented/delayed the development of resistance in melanomaBRAF(V600E)/CSPG4+ cells to PLX4032, and (3) the mechanism of action of the combination therapy caused a down-regulation in multiple signaling pathways. This study provides a foundation for future investigations designed to improve BRAF inhibitor effectiveness in vitro and in vivo for treating melanomaBRAF(V600E)/CSPG4+ cells in combination with a CSPG4-specific mAb.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. MacKie RM, Hauschild A, Eggermont AM. Epidemiology of invasive cutaneous melanoma. Ann Oncol. 2009;20(Suppl 6):1–7.

    Google Scholar 

  2. Cooper JS. Radiation therapy of malignant melanoma. Dermatol Clin. 2002;20:713–6.

    Article  PubMed  Google Scholar 

  3. Cascinelli N, Santinami M, Maurichi A, Patuzzo R, Pennacchioli E. World Health Organization experience in the treatment of melanoma. Surg Clin North Am. 2003;83:405–16.

    Article  PubMed  Google Scholar 

  4. Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010;363:809–19.

    Article  PubMed  CAS  Google Scholar 

  5. Flaherty KT, McArthur G. BRAF, a target in melanoma: implications for solid tumor drug development. Cancer. 2010;116:4902–13.

    Article  PubMed  CAS  Google Scholar 

  6. Gossage L, Eisen T. Targeting multiple kinase pathways: a change in paradigm. Clin Cancer Res. 2010;16:1973–8.

    Article  PubMed  CAS  Google Scholar 

  7. Smalley KS, Flaherty KT. Integrating BRAF/MEK inhibitors into combination therapy for melanoma. Br J Cancer. 2009;100:431–5.

    Article  PubMed  CAS  Google Scholar 

  8. Montagut C, Sharma SV, Shioda T, et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008;68:4853–61.

    Article  PubMed  CAS  Google Scholar 

  9. Janne PA, Gray N, Settleman J. Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. Nat Rev Drug Discov. 2009;8:709–23.

    Article  PubMed  CAS  Google Scholar 

  10. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature. 2010;464:427–30.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  12. Johannessen CM, Boehm JS, Kim SY, et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010;468:968–72.

    Article  PubMed  CAS  Google Scholar 

  13. Campoli M, Ferris R, Ferrone S, Wang X. Immunotherapy of malignant disease with tumor antigen-specific monoclonal antibodies. Clin Cancer Res. 2010;16:11–20.

    Article  PubMed  CAS  Google Scholar 

  14. Wang X, Osada T, Wang Y, et al. CSPG4 protein as a new target for the antibody-based immunotherapy of triple-negative breast cancer. J Natl Cancer Inst. 2010;102:1496–512.

    Article  PubMed  Google Scholar 

  15. Wang X, Wang Y, Yu L, et al. CSPG4 in cancer: multiple roles. Curr Mol Med. 2010;10:419–29.

    Article  PubMed  CAS  Google Scholar 

  16. Yang J, Price MA, Neudauer CL, et al. Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms. J Cell Biol. 2004;165:881–91.

    Article  PubMed  CAS  Google Scholar 

  17. Yang J, Price MA, Li GY, et al. Melanoma proteoglycan modifies gene expression to stimulate tumor cell motility, growth, and epithelial-to-mesenchymal transition. Cancer Res. 2009;69:7538–47.

    Article  PubMed  CAS  Google Scholar 

  18. Bao W, Stromblad S. Integrin alphav-mediated inactivation of p53 controls a MEK1-dependent melanoma cell survival pathway in three-dimensional collagen. J Cell Biol. 2004;167:745–56.

    Article  PubMed  CAS  Google Scholar 

  19. Schrama D, Keller G, Houben R, et al. BRAFV600E mutations in malignant melanoma are associated with increased expressions of BAALC. J Carcinog 2008;7:1.

    Google Scholar 

  20. Sondergaard JN, Nazarian R, Wang Q, et al. Differential sensitivity of melanoma cell lines with BRAFV600E mutation to the specific Raf inhibitor PLX4032. J Transl Med 2010;8:39.

    Google Scholar 

  21. Yang H, Higgins B, Kolinsky K, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res. 2010;70:5518–27.

    Article  PubMed  CAS  Google Scholar 

  22. O’Reilly KE, Warycha M, Davies MA, et al. Phosphorylated 4E-BP1 is associated with poor survival in melanoma. Clin Cancer Res. 2009;15:2872–8.

    Article  PubMed  Google Scholar 

  23. Domenzain-Reyna C, Hernandez D, Miquel-Serra L, et al. Structure and regulation of the versican promoter: the versican promoter is regulated by AP-1 and TCF transcription factors in invasive human melanoma cells. J Biol Chem. 2009;284:12306–17.

    Article  PubMed  CAS  Google Scholar 

  24. Bollag G, Hirth P, Tsai J, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature. 2010;467:596–9.

    Article  PubMed  CAS  Google Scholar 

  25. Campoli MR, Chang CC, Kageshita T, Wang X, McCarthy JB, Ferrone S. Human high molecular weight-melanoma-associated antigen (HMW-MAA): a melanoma cell surface chondroitin sulfate proteoglycan (MSCP) with biological and clinical significance. Crit Rev Immunol. 2004;24:267–96.

    Article  PubMed  CAS  Google Scholar 

  26. Perosa F, Ferrone S. Syngeneic antiidiotypic monoclonal antibodies to the murine anti-HLA-DR, DP monoclonal antibody CR11-462. Hum Immunol. 1988;23:255–69.

    Article  PubMed  CAS  Google Scholar 

  27. Temponi M, Kageshita T, Perosa F, Ono R, Okada H, Ferrone S. Purification of murine IgG monoclonal antibodies by precipitation with caprylic acid: comparison with other methods of purification. Hybridoma. 1989;8:85–95.

    Article  PubMed  CAS  Google Scholar 

  28. Burg MA, Nishiyama A, Stallcup WB. A central segment of the NG2 proteoglycan is critical for the ability of glioma cells to bind and migrate toward type VI collagen. Exp Cell Res. 1997;235:254–64.

    Article  PubMed  CAS  Google Scholar 

  29. Burg MA, Grako KA, Stallcup WB. Expression of the NG2 proteoglycan enhances the growth and metastatic properties of melanoma cells. J Cell Physiol. 1998;177:299–312.

    Article  PubMed  CAS  Google Scholar 

  30. Paraiso KH, Fedorenko IV, Cantini LP, et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010;102:1724–30.

    Article  PubMed  CAS  Google Scholar 

  31. Halaban R, Zhang W, Bacchiocchi A, et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res. 2010;23:190–200.

    Article  PubMed  CAS  Google Scholar 

  32. Villanueva J, Vultur A, Lee JT, et al. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3 K. Cancer Cell. 2010;18:683–95.

    Article  PubMed  CAS  Google Scholar 

  33. Flaherty K. 2011 [cited; Available from: http://www.dfhcc.harvard.edu/news/news/article/4126/334/?PHPSESSID=c84186b744715f955d507b9356d0f3b2.

  34. Mittelman A, Chen ZJ, Yang H, Wong GY, Ferrone S. Human high molecular weight melanoma-associated antigen (HMW-MAA) mimicry by mouse anti-idiotypic monoclonal antibody MK2-23: induction of humoral anti-HMW-MAA immunity and prolongation of survival in patients with stage IV melanoma. Proc Natl Acad Sci USA. 1992;89:466–70.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by Award P50CA121973 from the National Cancer Institute (NCI) and partially supported by Award 3P30CA047904 (the UPCI Cancer Center Support Grant) from the NCI.

Author information

Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    Ling Yu & Xinhui Wang

  2. Department of Surgery, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    Elvira Favoino & Yangyang Wang

  3. University of Pittsburgh Cancer Institute, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15232, USA

    Ling Yu, Elvira Favoino, Yangyang Wang, Yang Ma, Xiaojuan Deng & Xinhui Wang

Authors
  1. Ling Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elvira Favoino
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yangyang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiaojuan Deng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xinhui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xinhui Wang.

Additional information

Ling Yu and Elvira Favoino contributed equally to this research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yu, L., Favoino, E., Wang, Y. et al. The CSPG4-specific monoclonal antibody enhances and prolongs the effects of the BRAF inhibitor in melanoma cells. Immunol Res 50, 294–302 (2011). https://doi.org/10.1007/s12026-011-8232-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-011-8232-z

Keywords

Search

Navigation