Display options
Cite
Monsma DJ, Cherba DM, Eugster EE, et al. Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms. Am J Cancer Res. 2015;5(4):1507-18
Monsma, D. J., Cherba, D. M., Eugster, E. E., Dylewski, D. L., Davidson, P. T., Peterson, C. A., Borgman, A. S., Winn, M. E., Dykema, K. J., Webb, C. P., MacKeigan, J. P., Duesbery, N. S., Nickoloff, B. J., & Monks, N. R. (2015). Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms. American journal of cancer research, 5(4), 1507-18.
Monsma, David J, et al. "Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms." American journal of cancer research vol. 5,4 (2015): 1507-18.
Monsma DJ, Cherba DM, Eugster EE, Dylewski DL, Davidson PT, Peterson CA, Borgman AS, Winn ME, Dykema KJ, Webb CP, MacKeigan JP, Duesbery NS, Nickoloff BJ, Monks NR. Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms. Am J Cancer Res. 2015 Mar 15;5(4):1507-18. eCollection 2015. PMID: 26101714; PMCID: PMC4473327.
Copy Download .nbib Format: NLM
Share it on

Am J Cancer Res. 2015 Mar 15;5(4):1507-18. eCollection 2015.

Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms.

American journal of cancer research

David J Monsma, David M Cherba, Emily E Eugster, Dawna L Dylewski, Paula T Davidson, Chelsea A Peterson, Andrew S Borgman, Mary E Winn, Karl J Dykema, Craig P Webb, Jeffrey P MacKeigan, Nicholas S Duesbery, Brian J Nickoloff, Noel R Monks

Affiliations

  1. Vivarium and Transgenics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
  2. Bioinformatics and Biostatistics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
  3. Pathology and Biorepository Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
  4. Center for Translational Medicine, Van Andel Research Institute Grand Rapids, Michigan, USA.
  5. College of Human Medicine, Michigan State University Grand Rapids, Michigan, USA.
  6. NuMedi Palo Alto, California, USA.
  7. Laboratory of Systems Biology, Van Andel Research Institute Grand Rapids, Michigan, USA.
  8. Laboratory of Cancer and Developmental Cell Biology, Van Andel Research Institute Grand Rapids, Michigan, USA.
  9. Center for Translational Medicine, Van Andel Research Institute Grand Rapids, Michigan, USA ; College of Human Medicine, Michigan State University Grand Rapids, Michigan, USA.
  10. Center for Translational Medicine, Van Andel Research Institute Grand Rapids, Michigan, USA ; Current address: Medimmune, One MedImmune Way Gaithersburg, MD, 20878, USA.

PMID: 26101714 PMCID: PMC4473327

Abstract

Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF(V600E) models showed acquired drug resistance, one BRAF(V600E) model had a complete and durable response, and a BRAF(V600V) model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations.

Keywords: BRAF; MEK; Melanoma; Vemurafenib; drug resistance; patient derived xenografts (PDX)

References

  1. Nature. 2011 Nov 23;480(7377):387-90 - PubMed
  2. PLoS One. 2012;7(1):e29336 - PubMed
  3. Cancer Discov. 2014 Jan;4(1):61-8 - PubMed
  4. PLoS One. 2014 Nov 24;9(11):e113278 - PubMed
  5. PLoS One. 2013 Aug 20;8(8):e70826 - PubMed
  6. Nature. 2010 Dec 16;468(7326):968-72 - PubMed
  7. Melanoma Res. 2012 Dec;22(6):466-72 - PubMed
  8. Mol Cancer Ther. 2012 Apr;11(4):909-20 - PubMed
  9. Clin Ther. 2012 Jul;34(7):1474-86 - PubMed
  10. Clin Cancer Res. 2010 Mar 15;16(6):1924-37 - PubMed
  11. Clin Cancer Res. 2013 Oct 15;19(20):5749-57 - PubMed
  12. J Transl Med. 2012 Jun 18;10:125 - PubMed
  13. Mol Cancer Ther. 2012 Dec;11(12):2704-8 - PubMed
  14. N Engl J Med. 2010 Aug 26;363(9):809-19 - PubMed
  15. Nat Commun. 2012 Mar 06;3:724 - PubMed
  16. Cancer Manag Res. 2014 Sep 10;6:349-56 - PubMed
  17. Nature. 2013 Feb 14;494(7436):251-5 - PubMed
  18. Nature. 2010 Sep 30;467(7315):596-9 - PubMed
  19. J Clin Oncol. 2013 May 10;31(14 ):1767-74 - PubMed
  20. Nat Rev Drug Discov. 2011 Oct 31;10 (11):811-2 - PubMed
  21. Br J Dermatol. 2014 Jan;170(1):36-44 - PubMed
  22. Lab Invest. 2013 Aug;93(8):858-67 - PubMed
  23. N Engl J Med. 2011 Jun 30;364(26):2507-16 - PubMed
  24. N Engl J Med. 2013 Feb 28;368(9):842-51 - PubMed
  25. Lancet. 2012 Jul 28;380(9839):358-65 - PubMed
  26. Cancer Discov. 2014 Jan;4(1):80-93 - PubMed
  27. Sci Transl Med. 2011 Nov 30;3(111):111ra121 - PubMed
  28. Pigment Cell Melanoma Res. 2013 Jul;26(4):E8-E14 - PubMed
  29. Clin Exp Metastasis. 2012 Oct;29(7):775-96 - PubMed
  30. J Biol Chem. 2012 Dec 7;287(50):41797-807 - PubMed
  31. Cancer Chemother Pharmacol. 2011 Aug;68(2):547-52 - PubMed
  32. Nature. 2010 Dec 16;468(7326):973-7 - PubMed

Publication Types