Downregulation of PIK3CA via antibody-esiRNA-complexes suppresses human xenograft tumor growth

• Published in: PloS one 2018-07, Vol.13 (7), p.e0200163-e0200163
• Main Authors: Bäumer, Nicole, Rehkämper, Jan, Appel, Neele, Terheyden, Lisa, Hartmann, Wolfgang, Wardelmann, Eva, Buchholz, Frank, Müller-Tidow, Carsten, Berdel, Wolfgang E, Bäumer, Sebastian
• Format: Article
• Language: English
• Subjects: AKT protein; Biology and life sciences; c-Myc protein; Cancer; Cancer therapies; Care and treatment; Cell proliferation; Cellular signal transduction; Colorectal cancer; Colorectal carcinoma; Epidermal growth factor; Epidermal growth factor receptors; Genetic aspects; Genomes; Hematology; In vivo methods and tests; K-Ras protein; Medical prognosis; Medicine; Medicine and Health Sciences; Methods; Monoclonal antibodies; Mutation; Myc protein; Oncology; Pathology; Pools; Proteins; Research and analysis methods; Rodents; Signaling; siRNA; Targeted cancer therapy; Therapy; Tumor cells; Tumors; Xenografts; Xenotransplantation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0200163

Precision cancer therapy requires on the one hand detailed knowledge about a tumor's driver oncogenes and on the other hand an effective targeted therapy that specifically inhibits these oncogenes. While the determination of genomic landscape of a tumor has reached a very precise level, the respective therapy options are scarce. The application of small inhibitory (si) RNAs is a promising field of investigation. Here, we present the effective in vivo-treatment of colorectal cancer (CRC) xenograft tumors with antibody-complexed, endoribonuclease-prepared small inhibitory (esi)RNAs. We chose heterogeneous endoribonuclease-prepared siRNA pools (esiRNAs) against the frequently mutated genes PIK3CA and KRAS and coupled them to the anti-EGFR antibody cetuximab, which was internalized specifically into the tumor cells. esiRNA pools have been shown to exhibit superior specificity in target gene knockdown compared to classic siRNAs. We identified a significant decrease in tumor growth upon this treatment due to decreased tumor cell proliferation. The ex vivo-analysis of the xenograft CRC tumors revealed the expected downregulation of the intended direct targets PIK3CA and KRAS on protein level. Moreover, known downstream targets for EGFR signaling such as p-ERK, p-AKT, and c-MYC were decreased as well. We therefore propose the use of antibody-esiRNA complexes as a novel experimental treatment option against key components of the EGFR signaling cascade.