Secondary tumors arising in patients undergoing BRAF inhibitor therapy exhibit increased BRAF-CRAF heterodimerization

Lise Boussemart, Isabelle Girault, Hélène Malka-Mahieu, Christine Mateus, Emilie Routier, Margot Rubington, Nyam Kamsu-Kom, Marina Thomas, Gorana Tomasic, Sandrine Agoussi, Marie Breckler, Méllanie Laporte, Ludovic Lacroix, Alexander M. Eggermont, Andrea Cavalcanti, Florent Grange, Julien Adam, Stélphan Vagner, Caroline Robert

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

33 Citaten (Scopus)

Samenvatting

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. Cancer Res; 76(6); 1476-84. 2016 AACR.

Originele taal-2Engels
Pagina's (van-tot)1476-1484
Aantal pagina's9
TijdschriftCancer Research
Volume76
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - 15 mrt. 2016
Extern gepubliceerdJa

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