Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

Sushrut Kamerkar, Valerie S. LeBleu, Hikaru Sugimoto, Sujuan Yang, Carolina F. Ruivo, Sonia A. Melo, J. Jack Lee and Raghu Kalluri ()
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Sushrut Kamerkar: Metastasis Research Center, University of Texas MD Anderson Cancer Center
Valerie S. LeBleu: Metastasis Research Center, University of Texas MD Anderson Cancer Center
Hikaru Sugimoto: Metastasis Research Center, University of Texas MD Anderson Cancer Center
Sujuan Yang: Metastasis Research Center, University of Texas MD Anderson Cancer Center
Carolina F. Ruivo: Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Portugal (I3S)
Sonia A. Melo: Metastasis Research Center, University of Texas MD Anderson Cancer Center
J. Jack Lee: University of Texas MD Anderson Cancer Center
Raghu Kalluri: Metastasis Research Center, University of Texas MD Anderson Cancer Center

Nature, 2017, vol. 546, issue 7659, 498-503

Abstract: 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.

Date: 2017
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DOI: 10.1038/nature22341

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