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Updated: Nov 25, 2025
A Melanoma Patient-Derived Xenograft Model
Published on: May 20, 2019
The Genetic Evolution of Treatment-Resistant Cutaneous, Acral, and Uveal Melanomas
Alvin P Makohon-Moore1,2,3, Evan J Lipson4,5, Jody E Hooper5,6
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
Purpose:
Melanoma is a biologically heterogeneous disease composed of distinct clinicopathologic subtypes that frequently resist treatment. To explore the evolution of treatment resistance and metastasis, we used a combination of temporal and multilesional tumor sampling in conjunction with whole-exome sequencing of 110 tumors collected from 7 patients with cutaneous (n = 3), uveal (n = 2), and acral (n = 2) melanoma subtypes.
Experimental Design:
Primary tumors, metastases collected longitudinally, and autopsy tissues were interrogated. All but 1 patient died because of melanoma progression.
Results:
For each patient, we generated phylogenies and quantified the extent of genetic diversity among tumors, specifically among putative somatic alterations affecting therapeutic resistance.
Conclusions:
In 4 patients who received immunotherapy, we found 1-3 putative acquired and intrinsic resistance mechanisms coexisting in the same patient, including mechanisms that were shared by all tumors within each patient, suggesting that future therapies directed at overcoming intrinsic resistance mechanisms may be broadly effective.
Insights
Melanoma subtypes exhibit diverse resistance mechanisms. Shared resistance pathways across tumors suggest potential broad therapeutic targets for improving melanoma treatment outcomes.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- Melanoma is a heterogeneous cancer with distinct subtypes.
- Treatment resistance and metastasis are significant challenges in melanoma management.
Purpose of the Study:
- To investigate the evolution of treatment resistance and metastasis in melanoma.
- To analyze genetic diversity and identify resistance mechanisms across different melanoma subtypes.
Main Methods:
- Whole-exome sequencing of 110 tumors from 7 patients with cutaneous, uveal, and acral melanoma.
- Temporal and multilesional tumor sampling, including primary tumors, metastases, and autopsy tissues.
- Phylogenetic analysis to quantify genetic diversity and identify somatic alterations related to therapeutic resistance.
Main Results:
- Analysis revealed genetic diversity among tumors within individual melanoma patients.
- In patients receiving immunotherapy, 1-3 coexisting acquired and intrinsic resistance mechanisms were identified.
- Some resistance mechanisms were shared across all tumors within a patient, indicating potential common vulnerabilities.
Conclusions:
- Understanding melanoma's genetic heterogeneity is crucial for developing effective treatments.
- Shared resistance mechanisms present promising targets for broadly effective immunotherapies.
- Further research into intrinsic resistance pathways could lead to improved therapeutic strategies for melanoma.
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