Journal
CELL REPORTS
Volume 16, Issue 1, Pages 263-277Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2016.05.064
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Funding
- Dutch Cancer Society [NKI-2013-5799]
- European Research Council (ERC)
- Netherlands Organization for Scientific Research (NWO) [723.012.102]
- National Roadmap Large-scale Research Facilities of the Netherlands [184.032.201]
- Cancer Research UK
- Wellcome Trust [WT098051]
- Josephine Nefkins Foundation
- Barcode for Life
- Queen Wilhelmina Award by the Dutch Cancer Society
- Cancer Research UK [13031] Funding Source: researchfish
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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 BRAF(V600E), NRAS(Q61), or BRAF(WT)/NRAS(WT) 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 BRAF(V600E) protein harboring a kinase domain duplication (BRAF(V600E/DK)) in similar to 10% of the cases, both in PDXs and in an independent patient cohort. While BRAF(V600E/DK) depletion restored sensitivity to BRAF inhibition, a pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/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.
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