Antibody-Mediated Delivery of Anti–KRAS-siRNA In Vivo Overcomes Therapy Resistance in Colon Cancer
S Bäumer, N Bäumer, N Appel, L Terheyden… - Clinical Cancer …, 2015 - AACR
S Bäumer, N Bäumer, N Appel, L Terheyden, J Fremerey, S Schelhaas, E Wardelmann…
Clinical Cancer Research, 2015•AACRPurpose: 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 …
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 …
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. Clin Cancer Res; 21(6); 1383–94. ©2015 AACR.
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