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A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
Evolving Acquired Vemurafenib Resistance in a BRAF V600E Mutant Melanoma PDTX Model to Reveal New Potential Targets
József Tóvári1,2, Diána Vári-Mező1,2, Sára Eszter Surguta1,2
1Department of Experimental Pharmacology, National Institute of Oncology, 1122 Budapest, Hungary.
Abstract:
Malignant melanoma is challenging to treat, and metastatic cases need chemotherapy strategies. Targeted inhibition of commonly mutant BRAF V600E by inhibitors is efficient but eventually leads to resistance and progression in the vast majority of cases. Numerous studies investigated the mechanisms of resistance in melanoma cell lines, and an increasing number of in vivo or clinical data are accumulating. In most cases, bypassing BRAF and resulting reactivation of the MAPK signaling, as well as alternative PI3K-AKT signaling activation are reported. However, several unique changes were also shown. We developed and used a patient-derived tumor xenograft (PDTX) model to screen resistance evolution in mice in vivo, maintaining tumor heterogeneity. Our results showed no substantial activation of the canonical pathways; however, RNAseq and qPCR data revealed several altered genes, such as GPR39, CD27, SLC15A3, IFI27, PDGFA, and ABCB1. Surprisingly, p53 activity, leading to apoptotic cell death, was unchanged. The found biomarkers can confer resistance in a subset of melanoma patients via immune modulation, microenvironment changes, or drug elimination. Our resistance model can be further used in testing specific inhibitors that could be used in future drug development, and combination therapy testing that can overcome inhibitor resistance in melanoma.
Insights
Targeted melanoma therapy resistance can involve unique genetic changes, not just pathway reactivation. A patient-derived xenograft model identified novel resistance biomarkers, aiding future drug development for metastatic melanoma.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Malignant melanoma, especially metastatic cases, presents treatment challenges, often requiring chemotherapy.
- Targeted BRAF V600E inhibition is effective but frequently leads to drug resistance and disease progression.
- Existing research on resistance mechanisms primarily focuses on cell line studies, with limited in vivo data.
Purpose of the Study:
- To investigate resistance mechanisms to BRAF inhibitors in melanoma using a patient-derived tumor xenograft (PDTX) model.
- To identify novel genetic alterations and biomarkers associated with treatment resistance in vivo.
- To establish a preclinical model for evaluating strategies to overcome inhibitor resistance.
Main Methods:
- Development and utilization of a patient-derived tumor xenograft (PDTX) model to mimic melanoma heterogeneity in vivo.
- Application of RNA sequencing (RNAseq) and quantitative polymerase chain reaction (qPCR) to analyze gene expression changes in resistant tumors.
- Assessment of canonical signaling pathway activation (MAPK, PI3K-AKT) and p53 activity.
Main Results:
- The PDTX model demonstrated resistance evolution without substantial activation of canonical MAPK or PI3K-AKT pathways.
- RNAseq and qPCR identified several differentially expressed genes, including GPR39, CD27, SLC15A3, IFI27, PDGFA, and ABCB1.
- p53 activity and subsequent apoptotic cell death remained unchanged in the resistant tumors.
Conclusions:
- Identified genes may contribute to melanoma treatment resistance through mechanisms like immune modulation, microenvironment alteration, or drug efflux.
- The developed PDTX model serves as a valuable platform for future drug development and combination therapy testing to overcome BRAF inhibitor resistance.
- Novel biomarkers discovered could potentially guide personalized treatment strategies for subsets of melanoma patients.
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