Abstract
Lung cancer is the major cause of cancer-related deaths globally. Mutant KRAS is a feature of 15–50% of lung cancer cases and represents one of the most prevalent oncogenic drivers in this disease. Unfortunately, although much effort has been spent on searching for small molecule inhibitors of KRAS, KRAS gene has proven extraordinarily difficult to target by current pharmacological agents. In the present study, we developed an alternative strategy to silence the so-called untargetable and undruggable KRAS gene by employing exosome-mediated siRNA delivery. Particularly, we reprogrammed HEK293T cells to simultaneously express KRAS siRNA and Lamp2b, an exosomal membrane protein, in fusion with a tumor-penetrating internalizing RGD (iRGD) peptide (CRGDKGPDC), and then purified the tumor-targeting exosomes as KRAS siRNA delivery system. In agreement with the study design, intravenously injected iRGD-exosomes specifically targeted to tumor tissues in vivo. The therapeutic potential was revealed by the strong inhibition of tumor growth in a mouse model after intravenous injection of KRAS siRNA encapsulated in iRGD-exosomes. In conclusion, our results indicate that iRGD-tagged exosomes is an ideal delivery agent to transport KRAS siRNAs for lung cancer treatment. As an extension of this finding, the vast majority of mutated genes that are difficult to target by current pharmacological agents will be targetable and druggable in the future.
Highlights
Lung cancer is diagnosed at the highest frequency and leads to the highest mortality amongst all cancers [1]
Characterization of the redesigned internalizing RGD (iRGD)-exosomes loaded with Kirsten Rat Sarcoma viral oncogene homolog (KRAS) small interfering RNA (siRNA) We firstly designed a siRNA sequence targeting to the coding sequence homologue in both mouse and human KRAS
After collecting exosomes from HEK293T cells that express siRNA-KRAS/iRGD plasmid and injecting the redesigned exosomes into tumor-bearing mice, the iRGD tag that was engineered to be expressed on the exosomal membrane would guide the exosomes to tumor cells to release KRAS siRNA
Summary
Lung cancer is diagnosed at the highest frequency and leads to the highest mortality amongst all cancers [1]. Oncogenic mutations such as EGFR and EML4-ALK have been intensively investigated as targets of personalized lung cancer therapy. One of the commonest mutant genes in lung cancer cells is the Kirsten Rat Sarcoma viral oncogene homolog (KRAS) [2]. KRAS is a prominent oncogene because it can transform normal cells into malignant cells, when harboring an activating mutation in codon 12 or 13 [5]. Abnormal overexpression and somatic activating mutations in KRAS are universal in many cancer types, including majority of the pancreatic cancer (70–90%) [6], 30–60% of colon cancer [7] and 15–50% of lung cancer patients [8]. Much effort has been spent, KRAS has remained an untargetable and undruggable oncogene, possibly due to the absence of allosteric binding sites or activation of parallel signaling pathways that provide compensatory signals
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