Date: 2022-09-26 17:00 ~ 19:00
Speaker: Ju-Hong Jeon (Dept. of Biomedical Sciences, SNU)
Professor: 생명과학부
Location: 대면 | 목암홀(Mokam Hall) https://snu-ac-kr.zoom.us/j/94428091882
Old drug, new action: Crizotinib attenuates cancer metastasis by inhibiting TGFβ signaling in non-
small cell lung cancer cells
Abstract
Crizotinib is a clinically approved tyrosine kinase inhibitor for the treatment of patients with locally
advanced or metastatic non-small cell lung cancer (NSCLC) harboring EML4-ALK fusion. Crizotinib
was originally developed as an inhibitor of MET (HGF receptor), which is involved in the metastatic
cascade. However, little is known about whether crizotinib inhibits tumor metastasis in NSCLC cells.
In this study, we found that crizotinib suppressed TGFβ signaling by blocking Smad phosphorylation
in an ALK/MET/RON/ROS1-independent manner in NSCLC cells. Molecular docking and in vitro
enzyme activity assays showed that crizotinib directly inhibited the kinase activity of TGFβ receptor I
through a competitive inhibition mode. Cell tracking, scratch wound, and transwell migration assays
showed that crizotinib simultaneously inhibited TGFβ- and HGF-mediated NSCLC cell migration and
invasion. In addition, in vivo bioluminescence imaging analysis showed that crizotinib suppressed the
metastatic capacity of NSCLC cells. Our results demonstrate that crizotinib attenuates cancer
metastasis by inhibiting TGFβ signaling in NSCLC cells. Therefore, our findings will help to advance
our understanding of the anticancer action of crizotinib and provide insight into future clinical
investigations.