Oncotarget

Research Papers:

Crizotinib exhibits antitumor activity by targeting ALK signaling not c-MET in pancreatic cancer

Hong Hua Yan _, Kyung Hee Jung, Mi Kwon Son, Zhenghuan Fang, Soo Jung Kim, Ye-Lim Ryu, Juyoung Kim, Mi-Hyun Kim and Soon-Sun Hong

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Oncotarget. 2014; 5:9150-9168. https://doi.org/10.18632/oncotarget.2363

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Abstract

Hong Hua Yan1*, Kyung Hee Jung1*, Mi Kwon Son1, Zhenghuan Fang1, Soo Jung Kim1, Ye-Lim Ryu1, Juyoung Kim1, Mi-Hyun Kim2, Soon-Sun Hong1

1College of Medicine, Inha University, 3-ga, Sinheung-dong, Jung-gu, Incheon 400-712, Republic of Korea;

2School of Biological & Chemical Engineering, Yanbian University of Science & Technology, Beishan St., Yanji City, Jilin Prov., 133000, China

*These authors equally contributed to this work.

Correspondence to:

Dr. Soon-Sun Hong, e-mail: [email protected]

Key words: Crizotinib, Pancreatic cancer, c-MET, ALK, Apoptosis

Received: May 22, 2014     Accepted: August 18, 2014     Published: August 23, 2014

ABSTRACT

Crizotinib, a c-MET/ALK inhibitor, has exhibited antitumor efficacy in different types of cancers. However, studies regarding Crizotinib in pancreatic cancer have been limited. Thus, we investigated the effect of Crizotinib on pancreatic cancer and its mechanism of action. Crizotinib strongly suppressed the growth and proliferation of pancreatic cancer cells in a dose-dependent manner. Also, it induced apoptosis by modulating its related factors. In the study, with regard to the mechanism of action, Crizotinib did not inhibit c-MET expression on pancreatic cancer cells; instead, it specifically inhibited the activity of ALK, which was identified to be highly expressed on various pancreatic cancer cells and tissues in our study. In 42 different receptor tyrosine kinase (RTKs) array, Crizotinib also strongly inhibited the expression of activated ALK in pancreatic cancer cells, modulating its downstream mediators such as STAT3, AKT, and ERK. Furthermore, Crizotinib inhibited angiogenesis in a mouse Matrigel plug assay as well as the progression of tumor growth in a mouse xenograft model. Taken together, our investigation shows that Crizotinib inhibits the ALK signaling pathway in pancreatic cancer, resulting in cell growth/angiogenesis inhibition and apoptosis induction. We suggest that Crizotinib might be used as a novel therapeutic drug for treating pancreatic cancer.


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