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Updated: Mar 19, 2026
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
BRAF(V600E) Kinase Domain Duplication Identified in Therapy-Refractory Melanoma Patient-Derived Xenografts
Kristel Kemper1, Oscar Krijgsman1, Xiangjun Kong1
1Division of Molecular Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Abstract:
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 ∼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.
Insights
Patient-derived xenografts reveal a BRAF kinase domain duplication (BRAF(V600E/DK)) as a resistance mechanism in melanoma. Pan-RAF dimerization inhibitors show promise for treating this BRAF-mutated melanoma subtype.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Melanoma treatment landscape is evolving with targeted therapies.
- Drug resistance remains a significant challenge, limiting durable clinical responses.
- Need for robust in vivo models for studying resistance and optimizing treatments.
Purpose of the Study:
- Establish patient-derived xenografts (PDXs) for melanoma resistance studies.
- Identify mechanisms of resistance to BRAF inhibitors.
- Evaluate potential therapeutic strategies for resistant melanoma.
Main Methods:
- Generated a collection of PDXs from melanoma metastases (BRAF(V600E), NRAS(Q61), BRAF(WT)/NRAS(WT)) before and after BRAF inhibitor treatment.
- Screened PDX tumor lysates to identify resistance mechanisms.
- Validated findings in an independent patient cohort.
Main Results:
- Identified a BRAF kinase domain duplication (BRAF(V600E/DK)) in approximately 10% of cases.
- Depletion of BRAF(V600E/DK) restored sensitivity to BRAF inhibition.
- A pan-RAF dimerization inhibitor effectively eliminated BRAF(V600E/DK)-expressing melanoma cells.
Conclusions:
- The PDX platform is valuable for mechanistic drug resistance studies and treatment optimization in melanoma.
- BRAF kinase domain duplication is a novel resistance mechanism in melanoma.
- BRAF dimerization inhibitors warrant clinical validation for patients with BRAF(V600E/DK) melanoma.
