PUBLICATION
Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment
- Authors
- Smith, E.A., Belote, R.L., Cruz, N.M., Moustafa, T.E., Becker, C.A., Jiang, A., Alizada, S., Prokofyeva, A., Chan, T.Y., Seasor, T.A., Balatico, M., Cortes-Sanchez, E., Lum, D.H., Hyngstrom, J.R., Zeng, H., Deacon, D.C., Grossmann, A.H., White, R.M., Zangle, T.A., Judson-Torres, R.L.
- ID
- ZDB-PUB-241204-8
- Date
- 2024
- Source
- Journal of experimental & clinical cancer research : CR 43: 317317 (Journal)
- Registered Authors
- White, Richard M.
- Keywords
- none
- MeSH Terms
-
- Skin Neoplasms/drug therapy
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
- Xenograft Model Antitumor Assays
- Cell Line, Tumor
- Mice
- Tumor Microenvironment*/drug effects
- Protein Kinase Inhibitors*/pharmacology
- Protein Kinase Inhibitors*/therapeutic use
- Melanoma*/drug therapy
- Melanoma*/genetics
- Melanoma*/metabolism
- Melanoma*/pathology
- Zebrafish*
- Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
- Receptor Protein-Tyrosine Kinases/metabolism
- Humans
- Disease Models, Animal
- Animals
- PubMed
- 39627834 Full text @ J. Exp. Clin. Cancer Res.
Citation
Smith, E.A., Belote, R.L., Cruz, N.M., Moustafa, T.E., Becker, C.A., Jiang, A., Alizada, S., Prokofyeva, A., Chan, T.Y., Seasor, T.A., Balatico, M., Cortes-Sanchez, E., Lum, D.H., Hyngstrom, J.R., Zeng, H., Deacon, D.C., Grossmann, A.H., White, R.M., Zangle, T.A., Judson-Torres, R.L. (2024) Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment. Journal of experimental & clinical cancer research : CR. 43:317317.
Abstract
Background Acral melanoma (AM) is an aggressive melanoma variant that arises from palmar, plantar, and nail unit melanocytes. Compared to non-acral cutaneous melanoma (CM), AM is biologically distinct, has an equal incidence across genetic ancestries, typically presents in advanced stage disease, is less responsive to therapy, and has an overall worse prognosis.
Methods An independent analysis of published sequencing data was performed to evaluate the frequency of receptor tyrosine kinase (RTK) ligands and adapter protein gene variants and expression. To target these genetic variants, a zebrafish acral melanoma model and preclinical patient-derived xenograft (PDX) mouse models were treated with a panel of RTK inhibitors. Residual PDX tumors were evaluated for changes in proliferation, vasculature, necrosis, and ferroptosis by histology and immunohistochemistry.
Results RTK ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. Dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration in zebrafish, and the potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM PDX tumors but only slows tumor growth in CM models. Unlike other multi-RTK inhibitors, Lenvatinib is not directly cytotoxic to dissociated AM PDX tumor cells and instead disrupts tumor architecture and vascular networks.
Conclusion Considering the great difficulty in establishing AM cell culture lines, these findings suggest that AM may be more sensitive to microenvironment perturbations than CM. In conclusion, dual FGFR/VEGFR inhibition may be a viable therapeutic strategy that targets the unique biology of AM.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping