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Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

Authors :
Raghu Kalluri
J. Jack Lee
Sonia A. Melo
Valerie S. LeBleu
Sushrut Kamerkar
Hikaru Sugimoto
Sujuan Yang
Carolina F. Ruivo
Source :
Nature. 546:498-503
Publication Year :
2017
Publisher :
Springer Science and Business Media LLC, 2017.

Abstract

The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes are extracellular vesicles generated by all cells, and are naturally present in the blood. Here we show that enhanced retention of exosomes, compared to liposomes, in the circulation of mice is likely due to CD47-mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry short interfering RNA or short hairpin RNA specific to oncogenic KrasG12D, a common mutation in pancreatic cancer. Compared to liposomes, the engineered exosomes (known as iExosomes) target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. Treatment with iExosomes suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased overall survival. Our results demonstrate an approach for direct and specific targeting of oncogenic KRAS in tumours using iExosomes.

Details

ISSN :
14764687 and 00280836
Volume :
546
Database :
OpenAIRE
Journal :
Nature
Accession number :
edsair.doi.dedup.....680f8372c129291cd3eb0c14f9393c36
Full Text :
https://doi.org/10.1038/nature22341