Mutated BRAF emerges as a major effector of recurrence in a murine melanoma model after treatment with immunomodulatory agents

Shane Zaidi, Miran Blanchard, Kevin Shim, Elizabeth Ilett, Karishma Rajani, Christopher Parrish, Nicolas Boisgerault, Tim Kottke, Jill Thompson, Esteban Celis, Jose Pulido, Peter Selby, Hardev Pandha, Alan Melcher, Kevin Harrington, Richard Vile

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

We used a VSV-cDNA library to treat recurrent melanoma, identifying immunogenic antigens, allowing us to target recurrences with immunotherapy or chemotherapy. Primary B16 melanoma tumors were induced to regress by frontline therapy. Mice with recurrent tumors were treated with VSV-cDNA immunotherapy. A Th17 recall response was used to screen the VSV-cDNA library for individual viruses encoding rejection antigens, subsequently targeted using immunotherapy or chemotherapy. Recurrent tumors were effectively treated with a VSV-cDNA library using cDNA from recurrent B16 tumors. Recurrence-associated rejection antigens identified included Topoisomerase-IIα, YB-1, cdc7 kinase, and BRAF. Fourteen out of 16 recurrent tumors carried BRAF mutations (595-605 region) following frontline therapy, even though the parental B16 tumors were BRAF wild type. The emergence of mutated BRAF-containing recurrences served as an excellent target for BRAF-specific immune-(VSV-BRAF), or chemo-(PLX-4720) therapies. Successful PLX-4720 therapy of recurrent tumors was associated with the development of a broad spectrum of T-cell responses. VSV-cDNA technology can be used to identify recurrence specific antigens. Emergence of mutated BRAF may be a major effector of melanoma recurrence which could serve as a target for chemo or immune therapy. This study suggests a rationale for offering patients with initially wild-type BRAF melanomas an additional biopsy to screen for mutant BRAF upon recurrence.

Original languageEnglish (US)
Pages (from-to)845-856
Number of pages12
JournalMolecular Therapy
Volume23
Issue number5
DOIs
StatePublished - May 9 2015

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Melanoma
Recurrence
Gene Library
Neoplasms
Immunotherapy
Antigens
Complementary DNA
Therapeutics
Proto-Oncogene Proteins B-raf
Drug Therapy
Type II DNA Topoisomerase
Experimental Melanomas
Viruses
Technology
T-Lymphocytes
Biopsy
Mutation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Mutated BRAF emerges as a major effector of recurrence in a murine melanoma model after treatment with immunomodulatory agents. / Zaidi, Shane; Blanchard, Miran; Shim, Kevin; Ilett, Elizabeth; Rajani, Karishma; Parrish, Christopher; Boisgerault, Nicolas; Kottke, Tim; Thompson, Jill; Celis, Esteban; Pulido, Jose; Selby, Peter; Pandha, Hardev; Melcher, Alan; Harrington, Kevin; Vile, Richard.

In: Molecular Therapy, Vol. 23, No. 5, 09.05.2015, p. 845-856.

Research output: Contribution to journalArticle

Zaidi, S, Blanchard, M, Shim, K, Ilett, E, Rajani, K, Parrish, C, Boisgerault, N, Kottke, T, Thompson, J, Celis, E, Pulido, J, Selby, P, Pandha, H, Melcher, A, Harrington, K & Vile, R 2015, 'Mutated BRAF emerges as a major effector of recurrence in a murine melanoma model after treatment with immunomodulatory agents', Molecular Therapy, vol. 23, no. 5, pp. 845-856. https://doi.org/10.1038/mt.2014.253
Zaidi, Shane ; Blanchard, Miran ; Shim, Kevin ; Ilett, Elizabeth ; Rajani, Karishma ; Parrish, Christopher ; Boisgerault, Nicolas ; Kottke, Tim ; Thompson, Jill ; Celis, Esteban ; Pulido, Jose ; Selby, Peter ; Pandha, Hardev ; Melcher, Alan ; Harrington, Kevin ; Vile, Richard. / Mutated BRAF emerges as a major effector of recurrence in a murine melanoma model after treatment with immunomodulatory agents. In: Molecular Therapy. 2015 ; Vol. 23, No. 5. pp. 845-856.
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