Open AccessFocal adhesion kinase activation limits efficacy of Dasatinib in c‐Myc driven hepatocellular carcinoma
Author(s) -
Liu Xianqiong,
Song Xinhua,
Zhang Jie,
Xu Zhong,
Che Li,
Qiao Yu,
Ortiz Pedraza Yunuen,
Cigliano Antonio,
Pascale Rosa M.,
Calvisi Diego F.,
Liu Yanju,
Chen Xin
Publication year - 2018
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.1777
Subject(s) - dasatinib , hepatocellular carcinoma , cancer research , medicine , lyn , proto oncogene tyrosine protein kinase src , cell culture , focal adhesion , cell , oncology , chemistry , biology , imatinib , receptor , biochemistry , myeloid leukemia , genetics
Abstract Hepatocellular carcinoma ( HCC ) is a deadly malignancy with limited treatment options. Recently, it was found that Dasatinib treatment led to synthetic lethality in c‐Myc high‐expressing human cancer cells due to inhibition of p‐Lyn. Overexpression of c‐Myc is frequently seen in human HCC . We investigated the sensitivity to Dasatinib in vitro using HCC cell lines and in vivo using c‐Myc mouse HCC model. We found that HCC cell line responsiveness to Dasatinib varied significantly. However, there was no correlation between c‐Myc expression and IC 50 to Dasatinib. In c‐Myc‐induced HCC in mice, tumors continued to grow despite Dasatinib treatment, although the eventual tumor burden was lower in Dasatinib treatment cohort. Molecular analyses revealed that Dasatinib was effective in inhibiting p‐Src, but not p‐Lyn, in HCC . Importantly, we found that in HCC cell lines as well as c‐Myc mouse HCC , Dasatinib treatment induced up regulation of activated/phosphorylated (p)‐focal adhesion kinase( FAK ). Concomitant treatment of HCC cell lines with Dasatinib and FAK inhibitor prevented Dasatinib‐induced FAK activation, leading to stronger growth restraint. Altogether, our results suggest that Dasatinib may have limited efficacy as single agent for HCC treatment. Combined treatment with Dasatinib with FAK inhibitor might represent a novel therapeutic approach against HCC .