1. Intracellular KRAS-specific antibody enhances the anti-tumor efficacy of gemcitabine in pancreatic cancer by inducing endosomal escape.
- Author
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Lee, Ji Eun, Kang, Yeo Wool, Jung, Kyung Hee, Son, Mi Kwon, Shin, Seung-Min, Kim, Ji-Sun, Kim, Soo Jung, Fang, Zhenghuan, Yan, Hong Hua, Park, Jung Hee, Yoon, Young-Chan, Han, Boreum, Cheon, Min Ji, Woo, Min Gyu, Seo, Myung Sung, Lim, Joo Han, Kim, Yong-Sung, and Hong, Soon-Sun
- Subjects
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PANCREATIC cancer , *CELL adhesion molecules , *PANCREATIC intraepithelial neoplasia , *CANCER cells , *IMMUNOGLOBULINS , *EPITHELIAL cells , *PROTEIN metabolism , *PANCREATIC tumors , *PROTEINS , *RESEARCH , *GENETIC mutation , *CANCER invasiveness , *ANTHROPOMETRY , *ANIMAL experimentation , *RESEARCH methodology , *DEOXYCYTIDINE , *ANTINEOPLASTIC agents , *CELL physiology , *MEDICAL cooperation , *EVALUATION research , *ANTIMETABOLITES , *CELL motility , *COMPARATIVE studies , *DRUG synergism , *ENDOCYTOSIS , *CELL lines , *CYTOPLASM , *DRUG resistance in cancer cells , *MICE , *PHARMACODYNAMICS , *CHEMICAL inhibitors - Abstract
KRAS mutation is associated with the progression and growth of pancreatic cancer and contributes to chemo-resistance, which poses a significant clinical challenge in pancreatic cancer. Here, we developed a RT22-ep59 antibody (Ab) that directly targets the intracellularly activated GTP-bound form of oncogenic KRAS mutants after it is internalized into cytosol by endocytosis through tumor-associated receptor of extracellular epithelial cell adhesion molecule (EpCAM) and investigated its synergistic anticancer effects in the presence of gemcitabine in pancreatic cancer. We first observed that RT22-ep59 specifically recognized tumor-associated EpCAM and reached the cytosol by endosomal escape. In addition, the anticancer effect of RT22-ep59 was observed in the high-EpCAM-expressing pancreatic cancer cells and gemcitabine-resistant pancreatic cancer cells, but it had little effect on the low-EpCAM-expressing pancreatic cancer cells. Additionally, co-treatment with RT22-ep59 and gemcitabine synergistically inhibited cell viability, migration, and invasion in 3D-cultures and exhibited synergistic anticancer activity by inhibiting the RAF/ERK or PI3K/AKT pathways in cells with high-EpCAM expression. In an orthotopic mouse model, combined administration of RT22-ep59 and gemcitabine significantly inhibited tumor growth. Furthermore, the co-treatment suppressed cancer metastasis by blocking EMT signaling in vitro and in vivo. Our results demonstrated that RT22-ep59 synergistically increased the antitumor activity of gemcitabine by inhibiting RAS signaling by specifically targeting KRAS. This indicates that co-treatment with RT22-ep59 and gemcitabine might be considered a potential therapeutic strategy for pancreatic cancer patients harboring KRAS mutation. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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