Related Experiment Video
Updated: Apr 8, 2026
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Melanoma patient derived xenografts acquire distinct Vemurafenib resistance mechanisms
David J Monsma1, David M Cherba2, Emily E Eugster3
1Vivarium and Transgenics Core, Van Andel Research Institute Grand Rapids, Michigan, USA.
Abstract:
Variable clinical responses, tumor heterogeneity, and drug resistance reduce long-term survival outcomes for metastatic melanoma patients. To guide and accelerate drug development, we characterized tumor responses for five melanoma patient derived xenograft models treated with Vemurafenib. Three BRAF(V600E) models showed acquired drug resistance, one BRAF(V600E) model had a complete and durable response, and a BRAF(V600V) model was expectedly unresponsive. In progressing tumors, a variety of resistance mechanisms to BRAF inhibition were uncovered, including mutant BRAF alternative splicing, NRAS mutation, COT (MAP3K8) overexpression, and increased mutant BRAF gene amplification and copy number. The resistance mechanisms among the patient derived xenograft models were similar to the resistance pathways identified in clinical specimens from patients progressing on BRAF inhibitor therapy. In addition, there was both inter- and intra-patient heterogeneity in resistance mechanisms, accompanied by heterogeneous pERK expression immunostaining profiles. MEK monotherapy of Vemurafenib-resistant tumors caused toxicity and acquired drug resistance. However, tumors were eradicated when Vemurafenib was combined the MEK inhibitor. The diversity of drug responses among the xenograft models; the distinct mechanisms of resistance; and the ability to overcome resistance by the addition of a MEK inhibitor provide a scheduling rationale for clinical trials of next-generation drug combinations.
Insights
Vemurafenib treatment for metastatic melanoma shows varied responses. Combining Vemurafenib with a MEK inhibitor effectively eradicates tumors, offering a promising strategy for overcoming drug resistance in melanoma patients.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Metastatic melanoma presents challenges due to variable patient responses, tumor heterogeneity, and acquired drug resistance, limiting long-term survival.
- Understanding resistance mechanisms is crucial for developing effective therapeutic strategies and improving patient outcomes.
Purpose of the Study:
- To characterize tumor responses and resistance mechanisms in patient-derived xenograft (PDX) models of melanoma treated with Vemurafenib.
- To identify actionable resistance pathways and evaluate combination therapies to overcome BRAF inhibitor resistance.
Main Methods:
- Treatment of five melanoma PDX models with Vemurafenib, a BRAF inhibitor.
- Analysis of resistance mechanisms in progressing tumors, including genetic mutations, gene amplification, and protein expression.
- Evaluation of MEK inhibitor monotherapy and combination therapy with Vemurafenib in resistant models.
Main Results:
- BRAF(V600E) models exhibited acquired resistance, while one showed a complete response, and a BRAF(V600V) model was unresponsive.
- Identified resistance mechanisms include alternative BRAF splicing, NRAS mutations, COT overexpression, and BRAF gene amplification, mirroring clinical findings.
- MEK inhibitor monotherapy led to toxicity and resistance, whereas Vemurafenib combined with a MEK inhibitor eradicated tumors.
Conclusions:
- Melanoma patient-derived xenograft models recapitulate clinical resistance patterns to BRAF inhibitors.
- Tumor heterogeneity in resistance mechanisms necessitates combination therapies.
- Combining Vemurafenib with a MEK inhibitor demonstrates a viable strategy to overcome BRAF inhibitor resistance and offers a rationale for clinical trials.
Related Concept Videos
02:56Treatment Resistant Cancers
01:30Skin Cancer
Basal Cell Carcinoma (BCC): BCC is the most common type of skin cancer, accounting for about 80% of cases. It typically develops in...