Extracellular vesicle-mediated gene therapy targets BRAF-mutant colorectal cancer by inhibiting the MEK1/2-ERK1/2 pathway.

BACKGROUND

Patients with colorectal cancer (CRC) harboring BRAF mutation have a poor prognosis. The median survival time for patients with advanced BRAF-mutant CRC is only approximately one year. Owing to the insensitivity to standard chemotherapy, there are still no effective and highly specific treatment strategies available in clinical practice for CRC patients with BRAF mutation. Therefore, targeting the BRAF mutation site, researching and exploring novel targeted therapies are essential to improve the survival rate of patients with this CRC subtype.

AIM

This study aims to develop a precise therapeutic system for BRAF CRC, based on the carrier properties of extracellular vesicles (EVs) and gene therapy targeting BRAF.

METHOD

We first obtained engineered cells capable of stably producing EVs loaded with BRAF nucleic acid drugs (siBRAF). Next, BRAF-mutant and wild-type CRC cell lines, as well as corresponding subcutaneous and metastasis models, were used to evaluate the therapeutic efficacy of EVs-siBRAF and explored the mechanism. Notably, patient-derived xenograft (PDX) models, which share the same molecular characteristics, pathological features, and heterogeneity as patients do, were utilized to further explore the therapeutic efficacy and mechanisms.

RESULT

EVs-siBRAF specifically inhibited BRAF CRC but didn't affect BRAF wild-type CRC in vitro and vivo. EVs-siBRAF exerts its therapeutic effect by regulating the MEK1/2-ERK1/2 pathway, and it has demonstrated excellent therapeutic efficacy in PDX models.

CONCLUSION

The therapeutic EVs we constructed are effective and specific for the BRAF-mutant CRC. This study provides a novel strategy for the treatment of CRC patients with BRAF mutation.