1. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer
- Author
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Raghu Kalluri, J. Jack Lee, Sonia A. Melo, Valerie S. LeBleu, Sushrut Kamerkar, Hikaru Sugimoto, Sujuan Yang, and Carolina F. Ruivo
- Subjects
0301 basic medicine ,Small interfering RNA ,CD47 Antigen ,Biology ,Exosomes ,medicine.disease_cause ,Monocytes ,Proto-Oncogene Proteins p21(ras) ,Small hairpin RNA ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Pancreatic cancer ,medicine ,Animals ,Gene Silencing ,Neoplasm Metastasis ,RNA, Small Interfering ,Multidisciplinary ,CD47 ,Cancer ,Genetic Therapy ,medicine.disease ,Microvesicles ,3. Good health ,Pancreatic Neoplasms ,Survival Rate ,GTPase KRas ,Disease Models, Animal ,030104 developmental biology ,030220 oncology & carcinogenesis ,Liposomes ,Immunology ,Cancer research ,Pinocytosis ,Female ,KRAS - 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.
- Published
- 2017
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