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

Autor:	Smith EA; Department of Pathology, University of Utah, Salt Lake City, UT, USA., Belote RL; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA., Cruz NM; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Moustafa TE; Department of Chemical Engineering, University of Utah, Salt Lake City, UT, USA., Becker CA; Department of Dermatology, University of Utah, Salt Lake City, UT, USA., Jiang A; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA., Alizada S; Department of Chemical Engineering, University of Utah, Salt Lake City, UT, USA., Chan TY; Preclinical Research Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Seasor TA; Department of Pathology, University of Utah, Salt Lake City, UT, USA., Balatico M; Department of Pathology, University of Utah, Salt Lake City, UT, USA., Cortes-Sanchez E; Immuno Oncology Network Core, The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA., Lum DH; Preclinical Research Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., Hyngstrom JR; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA., Zeng H; Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.; Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Deacon DC; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Department of Dermatology, University of Utah, Salt Lake City, UT, USA., Grossmann AH; Department of Pathology, University of Utah, Salt Lake City, UT, USA.; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA., White RM; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Ludwig Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford UK., Zangle TA; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Department of Chemical Engineering, University of Utah, Salt Lake City, UT, USA., Judson-Torres RL; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.; Department of Dermatology, University of Utah, Salt Lake City, UT, USA.; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jun 17. Date of Electronic Publication: 2024 Jun 17.
DOI:	10.1101/2024.06.15.599116
Abstrakt:	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. Independent analysis of published genomic and transcriptomic sequencing identified that receptor tyrosine kinase (RTK) ligands and adapter proteins are frequently amplified, translocated, and/or overexpressed in AM. To target these unique genetic changes, a zebrafish acral melanoma model was exposed to a panel of narrow and broad spectrum multi-RTK inhibitors, revealing that dual FGFR/VEGFR inhibitors decrease acral-analogous melanocyte proliferation and migration. The potent pan-FGFR/VEGFR inhibitor, Lenvatinib, uniformly induces tumor regression in AM patient-derived xenograft (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. 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. Competing Interests: CONFLICT OF INTEREST STATEMENTS: The authors declare no conflict of interest.
Databáze:	MEDLINE
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