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- Title
Downregulation of PIK3CA via antibody-esiRNA-complexes suppresses human xenograft tumor growth.
- Authors
Bäumer, Nicole; Rehkämper, Jan; Appel, Neele; Terheyden, Lisa; Hartmann, Wolfgang; Wardelmann, Eva; Buchholz, Frank; Müller-Tidow, Carsten; Berdel, Wolfgang E.; Bäumer, Sebastian
- Abstract
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.
- Subjects
SMALL interfering RNA; TUMOR growth; ENDORIBONUCLEASES; PHOSPHATIDYLINOSITOL 3-kinases; CETUXIMAB; THERAPEUTICS
- Publication
PLoS ONE, 2018, Vol 13, Issue 7, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0200163