Extracellular Vesicle-mediated Gene Therapy Targets BRAF-mutant Colorectal Cancer by Inhibiting the MEK1/2-ERK1/2 Pathway

Overview

Journal J Nanobiotechnology

Publisher Biomed Central

Specialty Biotechnology

Date 2025 Feb 20

PMID 39979881

Authors

Di Wang

Liwei Wang

Wei Zhang

Kaicheng Xu

Liang Chen

Ziye Guo

Kaile Wu

Donghua Huang

Yubin Zhao

Minjun Yao

Liming Zheng

Chenyi Ye

Jisheng Ran

Wei Zhou

Xin Liu

Jianbin Xu

Affiliations

Soon will be listed here.

Abstract

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.

References

Jones J, Renfro L, Al-Shamsi H, Schrock A, Rankin A, Zhang B . BRAF Mutations Define a Clinically Distinct Molecular Subtype of Metastatic Colorectal Cancer. J Clin Oncol. 2017; 35(23):2624-2630. PMC: 5549454. DOI: 10.1200/JCO.2016.71.4394. View

De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G . Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010; 11(8):753-62. DOI: 10.1016/S1470-2045(10)70130-3. View

Ma W, Chen Y, Xiong W, Li W, Xu Z, Wang Y . STOML2 interacts with PHB through activating MAPK signaling pathway to promote colorectal Cancer proliferation. J Exp Clin Cancer Res. 2021; 40(1):359. PMC: 8591804. DOI: 10.1186/s13046-021-02116-0. View

Hidalgo M, Amant F, Biankin A, Budinska E, Byrne A, Caldas C . Patient-derived xenograft models: an emerging platform for translational cancer research. Cancer Discov. 2014; 4(9):998-1013. PMC: 4167608. DOI: 10.1158/2159-8290.CD-14-0001. View

Roccaro A, Sacco A, Maiso P, Azab A, Tai Y, Reagan M . BM mesenchymal stromal cell-derived exosomes facilitate multiple myeloma progression. J Clin Invest. 2013; 123(4):1542-55. PMC: 3613927. DOI: 10.1172/JCI66517. View

Jin H, Huang X, Pan Q, Ma N, Xie X, Wei Y . The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression. Nat Commun. 2024; 15(1):2551. PMC: 10957977. DOI: 10.1038/s41467-024-46521-3. View

Wang X, Zhang H, Bai M, Ning T, Ge S, Deng T . Exosomes Serve as Nanoparticles to Deliver Anti-miR-214 to Reverse Chemoresistance to Cisplatin in Gastric Cancer. Mol Ther. 2018; 26(3):774-783. PMC: 5910674. DOI: 10.1016/j.ymthe.2018.01.001. View

Tao S, Yuan T, Zhang Y, Yin W, Guo S, Zhang C . Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics. 2017; 7(1):180-195. PMC: 5196895. DOI: 10.7150/thno.17133. View

Wu S, Ju G, Du T, Zhu Y, Liu G . Microvesicles derived from human umbilical cord Wharton's jelly mesenchymal stem cells attenuate bladder tumor cell growth in vitro and in vivo. PLoS One. 2013; 8(4):e61366. PMC: 3625149. DOI: 10.1371/journal.pone.0061366. View

10.

Yaeger R, Corcoran R . Targeting Alterations in the RAF-MEK Pathway. Cancer Discov. 2019; 9(3):329-341. PMC: 6397699. DOI: 10.1158/2159-8290.CD-18-1321. View

11.

Lou G, Song X, Yang F, Wu S, Wang J, Chen Z . Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. J Hematol Oncol. 2015; 8:122. PMC: 4627430. DOI: 10.1186/s13045-015-0220-7. View

12.

Tran M, Gowda R, Sharma A, Park E, Adair J, Kester M . Targeting V600EB-Raf and Akt3 using nanoliposomal-small interfering RNA inhibits cutaneous melanocytic lesion development. Cancer Res. 2008; 68(18):7638-49. PMC: 3628540. DOI: 10.1158/0008-5472.CAN-07-6614. View

13.

Hertzman Johansson C, Egyhazi Brage S . BRAF inhibitors in cancer therapy. Pharmacol Ther. 2013; 142(2):176-82. DOI: 10.1016/j.pharmthera.2013.11.011. View

14.

Ding N, Cui X, Gao Z, Huang H, Wei X, Du Z . A triple combination of atorvastatin, celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors. Int J Oncol. 2014; 44(6):2139-45. PMC: 4063540. DOI: 10.3892/ijo.2014.2350. View

15.

Kang H, Fan J, Lin R, Elf S, Ji Q, Zhao L . Metabolic Rewiring by Oncogenic BRAF V600E Links Ketogenesis Pathway to BRAF-MEK1 Signaling. Mol Cell. 2015; 59(3):345-358. PMC: 4530073. DOI: 10.1016/j.molcel.2015.05.037. View

16.

Wang D, Zhang W, Zhang C, Wang L, Chen H, Xu J . Exosomal non-coding RNAs have a significant effect on tumor metastasis. Mol Ther Nucleic Acids. 2022; 29:16-35. PMC: 9207556. DOI: 10.1016/j.omtn.2022.05.034. View

17.

Falcone A, Ricci S, Brunetti I, Pfanner E, Allegrini G, Barbara C . Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo.... J Clin Oncol. 2007; 25(13):1670-6. DOI: 10.1200/JCO.2006.09.0928. View

18.

Derose Y, Wang G, Lin Y, Bernard P, Buys S, Ebbert M . Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes. Nat Med. 2011; 17(11):1514-20. PMC: 3553601. DOI: 10.1038/nm.2454. View

19.

Keysar S, Astling D, Anderson R, Vogler B, Bowles D, Morton J . A patient tumor transplant model of squamous cell cancer identifies PI3K inhibitors as candidate therapeutics in defined molecular bins. Mol Oncol. 2013; 7(4):776-90. PMC: 3760013. DOI: 10.1016/j.molonc.2013.03.004. View

20.

Bruno S, Collino F, Deregibus M, Grange C, Tetta C, Camussi G . Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev. 2012; 22(5):758-71. DOI: 10.1089/scd.2012.0304. View