title: Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents.
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.
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: Shane
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Miran
authors.initials: M
authors.lastname: Blanchard
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shim
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ilett
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Karishma
authors.initials: K
authors.lastname: Rajani
authors.affiliation: Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Parrish
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Boisgerault
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Tim
authors.initials: T
authors.lastname: Kottke
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Thompson
authors.affiliation: Cancer Immunology, Inflammation and Tolerance Program, Georgia Regents University Cancer Center, Augusta, Georgia, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Pulido
authors.affiliation: Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Selby
authors.affiliation: Leggett Building, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK.
authors.forename: Hardev
authors.initials: H
authors.lastname: Pandha
authors.affiliation: Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Melcher
authors.affiliation: Targeted Therapy Team, Division of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Harrington
authors.affiliation: Department of Molecular Medicine, Mayo Clinic, Rochester, Minnesota, USA; Targeted and Biological Therapies Group, Leeds Institute of Cancer and Pathology, St. James' University Hospital, Leeds, UK; Department of Immunology, Mayo Clinic, Rochester, Minnesota, USA. Electronic address: vile.richard@mayo.edu.
authors.forename: Richard
authors.initials: R
authors.lastname: Vile
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology; D001483:Base Sequence; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D015774:Ganciclovir / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D007155:Immunologic Factors / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D008546:Melanoma, Experimental; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009364:Neoplasm Recurrence, Local; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics*; D013937:Thymidine Kinase / Q000235:genetics
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D007155:Immunologic Factors; D013937:Thymidine Kinase; D048493:Proto-Oncogene Proteins B-raf; D015774:Ganciclovir