Open AccessDownregulation of PIK3CA via antibody-esiRNA-complexes suppresses human xenograft tumor growth
Author(s) -
Nicole Bäumer,
Jan Rehkämper,
Neele Appel,
Lisa Terheyden,
Wolfgang Hartmann,
Eva Wardelmann,
Frank Buchholz,
Carsten MüllerTidow,
Wolfgang E. Berdel,
Sebastian Bäumer
Publication year - 2018
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0200163
Subject(s) - kras , downregulation and upregulation , cancer research , cetuximab , gene knockdown , small interfering rna , protein kinase b , colorectal cancer , cancer , chemistry , mapk/erk pathway , in vivo , biology , medicine , signal transduction , transfection , cell culture , microbiology and biotechnology , gene , biochemistry , genetics
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.