TY - JOUR
T1 - Secondary tumors arising in patients undergoing BRAF inhibitor therapy exhibit increased BRAF-CRAF heterodimerization
AU - Boussemart, Lise
AU - Girault, Isabelle
AU - Malka-Mahieu, Hélène
AU - Mateus, Christine
AU - Routier, Emilie
AU - Rubington, Margot
AU - Kamsu-Kom, Nyam
AU - Thomas, Marina
AU - Tomasic, Gorana
AU - Agoussi, Sandrine
AU - Breckler, Marie
AU - Laporte, Méllanie
AU - Lacroix, Ludovic
AU - Eggermont, Alexander M.
AU - Cavalcanti, Andrea
AU - Grange, Florent
AU - Adam, Julien
AU - Vagner, Stélphan
AU - Robert, Caroline
N1 - Publisher Copyright:
©2016 American Association for Cancer Research.
PY - 2016/3/15
Y1 - 2016/3/15
N2 - 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.
AB - 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.
U2 - 10.1158/0008-5472.CAN-15-2900-T
DO - 10.1158/0008-5472.CAN-15-2900-T
M3 - Article
C2 - 26825172
AN - SCOPUS:84962148974
SN - 0008-5472
VL - 76
SP - 1476
EP - 1484
JO - Cancer Research
JF - Cancer Research
IS - 6
ER -
