title: Secondary Tumors Arising in Patients Undergoing BRAF Inhibitor Therapy Exhibit Increased BRAF-CRAF Heterodimerization.
abstract: BRAF inhibitors (BRAFi) elicit therapeutic responses in metastatic melanoma, but alarmingly, also induce the formation of secondary benign and malignant skin tumors. Here, we report the emergence and molecular characterization of 73 skin and extracutaneous tumors in 31 patients who underwent BRAFi therapy. The majority of patients presented with classic epidermal tumors such as verrucous papillomas, keratoacanthomas, and squamous cell carcinomas (SCC). However, 15 patients exhibited new or rapidly progressing tumors distinct from these classic subtypes, such as lymph node metastasis, new melanomas, and genital and oral mucosal SCCs. Genotyping of the tumors revealed that oncogenic RAS mutations were found in 58% of the evaluable tumor samples (38/66) and 49% of the control tumors from patients not treated with BRAFi (30/62). Notably, proximity ligation assays demonstrated that BRAF-CRAF heterodimerization was increased in fixed tumor samples from BRAFi-treated patients compared with untreated patients. Our findings reveal that BRAF-CRAF complex formation is significantly associated with BRAFi treatment, and may therefore serve as a useful biomarker of BRAFi-induced cutaneous and extracutaneous tumor formation.
authors.affiliation: Département de médecine oncologique, Gustave Roussy, Villejuif, France. INSERM, U981, Villejuif, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Boussemart
authors.affiliation: INSERM, U981, Villejuif, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Girault
authors.affiliation: INSERM, U981, Villejuif, France. Faculté de Médecine, Université Paris-Sud, Le Kremlin Bicetre, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Malka-Mahieu
authors.affiliation: Département de médecine oncologique, Gustave Roussy, Villejuif, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Département de médecine oncologique, Gustave Roussy, Villejuif, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Routier
authors.affiliation: INSERM, U981, Villejuif, France.
authors.forename: Margot
authors.initials: M
authors.lastname: Rubington
authors.affiliation: INSERM, U981, Villejuif, France.
authors.forename: Nyam
authors.initials: N
authors.lastname: Kamsu-Kom
authors.affiliation: Département de médecine oncologique, Gustave Roussy, Villejuif, France.
authors.forename: Marina
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Département de pathologie, Gustave Roussy, Villejuif, France.
authors.forename: Gorana
authors.initials: G
authors.lastname: Tomasic
authors.affiliation: INSERM, U981, Villejuif, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Agoussi
authors.affiliation: Laboratoire de Recherche Translationnelle et Centre de Ressources Biologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Breckler
authors.affiliation: Laboratoire de Recherche Translationnelle et Centre de Ressources Biologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Laporte
authors.affiliation: INSERM, U981, Villejuif, France. Laboratoire de Recherche Translationnelle et Centre de Ressources Biologiques, AMMICA, INSERM US23/CNRS UMS3655, Gustave Roussy, Villejuif, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Lacroix
authors.affiliation: Département de médecine oncologique, Gustave Roussy, Villejuif, France.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: Département de chirurgie, Gustave Roussy, Villejuif, France.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalcanti
authors.affiliation: Département de Dermatologie, CHU de Reims, Reims, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Grange
authors.affiliation: INSERM, U981, Villejuif, France. Module de Développement en Pathologie, SIRICSOCRATE, Gustave Roussy, Villejuif, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: INSERM, U981, Villejuif, France.
authors.forename: Stéphan
authors.initials: S
authors.lastname: Vagner
authors.affiliation: Département de médecine oncologique, Gustave Roussy, Villejuif, France. INSERM, U981, Villejuif, France. Faculté de Médecine, Université Paris-Sud, Le Kremlin Bicetre, France. caroline.robert@gustaveroussy.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019281:Dimerization; D005838:Genotype; D006801:Humans; D009154:Mutation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf