Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

• Type: Article in International Scientific Journal
• Date: 2017

Authors

Kamerkar, S (Author) Other; LeBleu, VS (Author) Other; Sugimoto, H (Author) Other; Yang, SJ (Author) Other; Ruivo, CF (Author) Other; Melo, SA (Author) FMUP; Lee, JJ (Author) Other; Kalluri, R (Author) Other

Journal

Title: Nature

Vol. 546

Pages: 498-+

ISSN: 0028-0836

Publisher: Springer Nature

Indexing

ISI Web of Knowledge - 1032 Citations

Scopus - 1066 Citations

Other information

Authenticus ID: P-00R-ATF

DOI: 10.1038/nature22341

Abstract (EN): 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.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 24