Oral administration of FAK inhibitor TAE226 inhibits the progression of peritoneal dissemination of colorectal cancer.
Peritoneal dissemination is one of the most terrible types of colorectal cancer progression. Focal adhesion kinase (FAK) plays a crucial role in the biological processes of cancer, such as cell attachment, migration, proliferation and survival, all of which are essential for the progression of peritoneal dissemination. Since we and other groups have reported that the inhibition of FAK activity exhibited a potent anticancer effect in several cancer models, we hypothesized that TAE226, a novel ATP-competitive tyrosine kinase inhibitor designed to target FAK, can prevent the occurrence and progression of peritoneal dissemination. In vitro, TAE226 greatly inhibited the proliferation and migration of HCT116 colon cancer cells, while their adhesion on the matrix surface was minimally inhibited when FAK activity and expression was suppressed by TAE226 and siRNA. In vivo, when HCT116 cells were intraperitoneally inoculated in mice, the cells could attach to the peritoneum and begin to grow within 24 h regardless of the pretreatment of cells with TAE226 or FAK-siRNA, suggesting that FAK is not essential, at least for the initial integrin-matrix contact. Interestingly, the treatment of mice before and after inoculation significantly suppressed cell attachment to the peritoneum. Furthermore, oral administration of TAE226 greatly reduced the size of disseminated tumors and prolonged survival in tumor-bearing mice. Taken together, a possible strategy for inhibiting peritoneal dissemination by targeting FAK with TAE226 appears to be applicable through anti-proliferative and anti-invasion/anti-migration mechanisms.
Department of Gastroenterological Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikatacho, Kita-ku, Okayama 700-8558, Japan.
Hui-fang
HF
Hao
Munenori
M
Takaoka
Xiao-hong
XH
Bao
Zhi-gang
ZG
Wang
Yasuko
Y
Tomono
Kazufumi
K
Sakurama
Toshiaki
T
Ohara
Takuya
T
Fukazawa
Tomoki
T
Yamatsuji
Toshiyoshi
T
Fujiwara
Yoshio
Y
Naomoto
D000284:Administration, Oral; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018450:Disease Progression; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009025:Morpholines / Q000008:administration & dosage*; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control; D010537:Peritoneum / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000235:genetics
D009025:Morpholines; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C524632:TAE226; D051416:Focal Adhesion Protein-Tyrosine Kinases