Open Access
Open access
Springer Nature
Journal of Experimental and Clinical Cancer Research
,  volume 43 ,  issue 1 ,  publication number 317

Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment

Eric A. Smith 1
, 
Rachel L Belote 2, 3
, 
Nelly M Cruz 4
, 
Tarek E Moustafa 5
, 
Carly A Becker 6
, 
Amanda Jiang 7
, 
Shukran Alizada 5
, 
Anastasia Prokofyeva 7
, 
Tsz Yin Chan 8
, 
Tori A Seasor 1
, 
Michael Balatico 1
, 
Emilio Cortes-Sanchez 9, 10
, 
David H Lum 8
, 
John R Hyngstrom 2, 10
, 
Hanlin Zeng 11, 12
, 
Dekker C Deacon 2, 6
, 
Allie H. Grossmann 1, 2
, 
Richard M. White 4, 13
, 
Thomas A Zangle 2, 5
, 
Robert L Judson-Torres 2, 6, 7
1
 
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Publication type: Journal Article
Publication date: 2024-12-03
Springer Nature
scimago Q1
wos Q1
SJR: 3.328
CiteScore: 20.2
Impact factor: 12.8
ISSN: 03929078, 17569966
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.

Found 
Found 

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GOST Copy
Smith E. A. et al. Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment // Journal of Experimental and Clinical Cancer Research. 2024. Vol. 43. No. 1. 317
GOST all authors (up to 50) Copy
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. Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment // Journal of Experimental and Clinical Cancer Research. 2024. Vol. 43. No. 1. 317
RIS |
Cite this
RIS Copy
TY - JOUR
DO - 10.1186/s13046-024-03234-1
UR - https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03234-1
TI - Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment
T2 - Journal of Experimental and Clinical Cancer Research
AU - Smith, Eric A.
AU - Belote, Rachel L
AU - Cruz, Nelly M
AU - Moustafa, Tarek E
AU - Becker, Carly A
AU - Jiang, Amanda
AU - Alizada, Shukran
AU - Prokofyeva, Anastasia
AU - Chan, Tsz Yin
AU - Seasor, Tori A
AU - Balatico, Michael
AU - Cortes-Sanchez, Emilio
AU - Lum, David H
AU - Hyngstrom, John R
AU - Zeng, Hanlin
AU - Deacon, Dekker C
AU - Grossmann, Allie H.
AU - White, Richard M.
AU - Zangle, Thomas A
AU - Judson-Torres, Robert L
PY - 2024
DA - 2024/12/03
PB - Springer Nature
IS - 1
VL - 43
PMID - 39627834
SN - 0392-9078
SN - 1756-9966
ER -
BibTex
Cite this
BibTex (up to 50 authors) Copy
@article{2024_Smith,
author = {Eric A. Smith and Rachel L Belote and Nelly M Cruz and Tarek E Moustafa and Carly A Becker and Amanda Jiang and Shukran Alizada and Anastasia Prokofyeva and Tsz Yin Chan and Tori A Seasor and Michael Balatico and Emilio Cortes-Sanchez and David H Lum and John R Hyngstrom and Hanlin Zeng and Dekker C Deacon and Allie H. Grossmann and Richard M. White and Thomas A Zangle and Robert L Judson-Torres},
title = {Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment},
journal = {Journal of Experimental and Clinical Cancer Research},
year = {2024},
volume = {43},
publisher = {Springer Nature},
month = {dec},
url = {https://jeccr.biomedcentral.com/articles/10.1186/s13046-024-03234-1},
number = {1},
pages = {317},
doi = {10.1186/s13046-024-03234-1}
}