BRAFV600E Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts
oleh: Kristel Kemper, Oscar Krijgsman, Xiangjun Kong, Paulien Cornelissen-Steijger, Aida Shahrabi, Fleur Weeber, Daphne L. van der Velden, Onno B. Bleijerveld, Thomas Kuilman, Roel J.C. Kluin, Chong Sun, Emile E. Voest, Young Seok Ju, Ton N.M. Schumacher, A.F. Maarten Altelaar, Ultan McDermott, David J. Adams, Christian U. Blank, John B. Haanen, Daniel S. Peeper
| Format: | Article |
|---|---|
| Diterbitkan: | Elsevier 2016-06-01 |
Deskripsi
The therapeutic landscape of melanoma is improving rapidly. Targeted inhibitors show promising results, but drug resistance often limits durable clinical responses. There is a need for in vivo systems that allow for mechanistic drug resistance studies and (combinatorial) treatment optimization. Therefore, we established a large collection of patient-derived xenografts (PDXs), derived from BRAFV600E, NRASQ61, or BRAFWT/NRASWT melanoma metastases prior to treatment with BRAF inhibitor and after resistance had occurred. Taking advantage of PDXs as a limitless source, we screened tumor lysates for resistance mechanisms. We identified a BRAFV600E protein harboring a kinase domain duplication (BRAFV600E/DK) in ∼10% of the cases, both in PDXs and in an independent patient cohort. While BRAFV600E/DK depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAFV600E/DK-expressing cells. These results illustrate the utility of this PDX platform and warrant clinical validation of BRAF dimerization inhibitors for this group of melanoma patients.