Targeting KRAS mutations may lead to effective new pancreatic cancer treatments.
Genetically modified exosomes may hold the key to treating pancreatic cancer.
Mutated KRAS is commonly linked to pancreatic cancer; however, despite this knowledge, it remains a challenging therapeutic target.
In a study published in Nature, investigators genetically modified exosomes as “iExosomes,” which deliver smaller RNA to specifically target mutant KRAS. The approach resulted in disease suppression and increased overall survival in mouse models.
“The engineered exosomes target oncogenic KRAS with an enhanced efficacy that is dependent on CD47, and is facilitated by micropinocytosis,” the authors wrote.
The investigators utilized the targeting method RNA interference (RNAi). They showed that the exosomes could serve as an efficient carrier of RNAi because their small size can easily travel across the cells and enter cells.
KRAS is mutated in 80% to 95% of pancreatic ductal adenocarcinomas (PDAC), and is the most common mutation in this cancer type. In the study, the investigators demonstrated that iExosomes could deliver siRNA and shRNA—–KRAS-specific targeting genetic material––more efficiently than their synthetic counterpart, iLiposomes.
“Our studies suggest that exomes exhibit a superior ability to deliver siRNA molecules and suppress aggressive pancreatic tumor growth when compared to liposomes,” said co-lead investigator Valerie LeBleu, PhD. “We also demonstrated that the presence of CD47 on exosomes’ allows for evasion from phagocytosis by the circulating monocytes.”
The CD47 is a protein involved in many cellular processes, and phagocytosis is a process by which macrophages digest cellular debris and foreign particles.
“CD47 basically initiates a ‘don’t eat me’ signal that inhibits phagocytosis,” said co-lead investigator Sushrut Kamerkar, PhD. “We identified how CD47 contributes to suppressing exosomes clearance from circulation, and enhancing their delivery to pancreatic cancer cells.”
Additionally, the results of the study show that the cellular process of micropinocytosis contributes to the uptake of exosomes in cancer cells with mutant KRAS.
“The increased number of exosomes reaching the pancreas may gain further advantage to enter KRAS-associated cancer cells as a result of enhanced micropinocytosis, which concurs with previous findings,” Kamerkar said. “Our results also support an efficient uptake of iExosomes despite the dense stroma in pancreatic tumors.
Further study is needed to gain a better understanding about whether exosomes entering cells via micropinocytosis have other features that could enhance their anti-tumor capabilities.”