Format

Send to

Choose Destination
Neoplasia. 2017 Nov;19(11):932-940. doi: 10.1016/j.neo.2017.07.002. Epub 2017 Sep 28.

Intercellular Resistance to BRAF Inhibition Can Be Mediated by Extracellular Vesicle-Associated PDGFRβ.

Author information

1
Olivia Newton-John Cancer Research Institute, Level 5 Olivia Newton-John Cancer and Wellness Centre, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; The Florey Institute for Neuroscience and Mental Health, 30 Royal Parade, Parkville, VIC 3052, Australia. Electronic address: ljvella@unimelb.edu.au.
2
Olivia Newton-John Cancer Research Institute, Level 5 Olivia Newton-John Cancer and Wellness Centre, Austin Health, Studley Road, Heidelberg, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Heidelberg, VIC 3084, Heidelberg.
3
Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3083, Australia.

Abstract

Treatment of BRAF mutant melanoma with kinase inhibitors has been associated with rapid tumor regression; however, this clinical benefit is short-lived, and most patients relapse. A number of studies suggest that the extracellular environment promotes BRAF inhibitor resistance and tumor progression. Extracellular vesicles, such as exosomes, are functional mediators in the extracellular environment. They are small vesicles known to carry a concentrated group of functional cargo and serve as intercellular communicators not only locally but also systemically. Increasingly, it is reported that extracellular vesicles facilitate the development of drug resistance in cancer; however, their role in BRAF inhibitor resistance in melanoma is unclear. Here we investigated if extracellular vesicles from BRAF inhibitor-resistant melanoma could influence drug sensitivity in recipient melanoma cells. We demonstrate that the resistance driver, PDGFRβ, can be transferred to recipient melanoma cells via extracellular vesicles, resulting in a dose-dependent activation of PI3K/AKT signaling and escape from MAPK pathway BRAF inhibition. These data suggest that the BRAF inhibitor-sensitive phenotype of metastatic melanoma can be altered by delivery of PDGFRβ by extracellular vesicles derived from neighboring drug-resistant melanoma cells.

PMID:
28963969
PMCID:
PMC5678363
DOI:
10.1016/j.neo.2017.07.002
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center