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  • Title: Antibody-mediated delivery of anti-KRAS-siRNA in vivo overcomes therapy resistance in colon cancer.
    Author: Bäumer S, Bäumer N, Appel N, Terheyden L, Fremerey J, Schelhaas S, Wardelmann E, Buchholz F, Berdel WE, Müller-Tidow C.
    Journal: Clin Cancer Res; 2015 Mar 15; 21(6):1383-94. PubMed ID: 25589625.
    Abstract:
    PURPOSE: KRAS mutations are frequent driver mutations in multiple cancers. KRAS mutations also induce anti-EGFR antibody resistance in adenocarcinoma such as colon cancer. The aim of this study was to overcome anti-EGFR antibody resistance by coupling the antibody to KRAS-specific siRNA. EXPERIMENTAL DESIGN: The anti-EGFR antibody was chemically coupled to siRNA. The resulting complex was tested for antibody binding efficiency, serum stability and ability to deliver siRNA to EGFR-expressing cells. Western blotting, viability, apoptosis, and colony formation assays were performed for efficacy evaluation in vitro. Furthermore, therapeutic activity of the antibody-KRAS-siRNA complexes was examined in in vivo xenograft mouse tumor models. RESULTS: Antibody-siRNA complexes were targeted and internalized via the EGFR receptor. Upon internalization, target gene expression was strongly and specifically repressed, followed by a reduced proliferation and viability, and induced apoptosis of the cells in vitro. Clonogenic growth of mutant KRAS-bearing cells was suppressed by KRAS-siRNA-anti-EGFR antibody complexes. In xenograft mouse models, anti-EGFR antibody-KRAS-siRNA complexes significantly slowed tumor growth in anti-EGFR-resistant cells. CONCLUSIONS: The coupling of siRNA against KRAS to anti-EGFR antibodies provides a novel therapy approach for KRAS-mutated EGFR-positive cancer cells in vitro and in vivo. These findings provide an innovative approach for cancer-specific siRNA application and for enhanced therapeutic potential of monoclonal antibody therapy and personalized treatment of cancer entities.
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