Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer

被引：2329

作者：

Kamerkar, Sushrut ^{[1
]}

LeBleu, Valerie S. ^{[1
]}

Sugimoto, Hikaru ^{[1
]}

Yang, Sujuan ^{[1
]}

Ruivo, Carolina F. ^{[2
,3
]}

Melo, Sonia A. ^{[1
,2
,3
]}

Lee, J. Jack ^{[4
]}

Kalluri, Raghu ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Metastasis Res Ctr, Dept Canc Biol, Houston, TX 77005 USA

[2] Univ Porto, Inst Invest & Inovacao Saude, Portugal I3S, P-4200 Oporto, Portugal

[3] Univ Porto, IPATIMUP, Inst Pathol & Mol Immunol, P-4200 Oporto, Portugal

[4] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77005 USA

来源：

NATURE | 2017年 / 546卷 / 7659期

关键词：

DUCTAL ADENOCARCINOMA; EXTRACELLULAR VESICLES; DRUG-DELIVERY; MOUSE MODEL; SIRNA; PROTEIN; CELLS; RAS; CHEMOTHERAPY; MACROPINOCYTOSIS;

D O I：

10.1038/nature22341

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页码：498 / +

页数：24

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