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Receptor tyrosine kinase inhibition leads to regression of acral melanoma by targeting the tumor microenvironment.
Smith, Eric A; Belote, Rachel L; Cruz, Nelly M; Moustafa, Tarek E; Becker, Carly A; Jiang, Amanda; Alizada, Shukran; Chan, Tsz Yin; Seasor, Tori A; Balatico, Michael; Cortes-Sanchez, Emilio; Lum, David H; Hyngstrom, John R; Zeng, Hanlin; Deacon, Dekker C; Grossmann, Allie H; White, Richard M; Zangle, Thomas A; Judson-Torres, Robert L.
Afiliación
  • 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.
  • Cruz NM; Department of Molecular Genetics, The Ohio State University, Columbus, OH, USA.
  • Moustafa TE; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • Becker CA; Department of Chemical Engineering, University of Utah, Salt Lake City, UT, USA.
  • Jiang A; Department of Dermatology, University of Utah, Salt Lake City, UT, USA.
  • Alizada S; Department of Oncological Sciences, University of Utah, Salt Lake City, UT, USA.
  • Chan TY; Department of Chemical Engineering, University of Utah, Salt Lake City, UT, USA.
  • Seasor TA; Preclinical Research Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Balatico M; Department of Pathology, University of Utah, Salt Lake City, UT, USA.
  • Cortes-Sanchez E; Department of Pathology, University of Utah, Salt Lake City, UT, USA.
  • Lum DH; Immuno Oncology Network Core, The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Hyngstrom JR; Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • Zeng H; Preclinical Research Resource, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Deacon DC; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Grossmann AH; Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT, USA.
  • White RM; Department of Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Zangle TA; Shanghai Institute of Precision Medicine, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Judson-Torres RL; The Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
bioRxiv ; 2024 Jun 17.
Article en En | MEDLINE | ID: mdl-38948879
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos