Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo.
Inhibiting the interaction of cMET and IGF-1R with FAK effectively reduces growth of pancreatic cancer cells in vitro and in vivo.
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DOI：
10.2174/1871520611313040009
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发表时间：
2013-05
影响因子：
2.8
通讯作者：
Hochwald SN
中科院分区：
文献类型：
--
作者：
Ucar DA;Magis AT;He DH;Lawrence NJ;Sebti SM;Kurenova E;Zajac-Kaye M;Zhang J;Hochwald SN
胰腺癌是最致命的疾病之一，目前尚无有效的治疗方法。此前，我们已经证明FAK在胰腺癌中过表达，并在癌细胞的生存和增殖中发挥关键作用。研究表明，FAK与cMET和IGF-1R等生长因子受体相互作用。作为一种新的治疗方法，我们针对FAK与生长因子受体的蛋白质相互作用来阻止肿瘤生长，改变信号通路，并使细胞对化疗敏感。我们选择了一种小分子化合物(INT2-31)，它通过破坏FAK与cMET和IGF-1R的相互作用来减少AKT的磷酸化。我们的结果表明，小分子化合物与FAK的相互作用降低了FAK Y397的磷酸化，而增加了FAK Y407的磷酸化，而不抑制FAK的激酶活性，并显著减少了AKT的下游信号。我们的先导化合物INT2-31在两个胰腺癌原位模型中显示出显著的抑制肿瘤细胞生长的作用。此外，在胰腺癌生长的直接新鲜活检异种移植模型中，INT2-31增加了对吉西他滨化疗的敏感性。
Pancreatic cancer is one of the most lethal diseases with no effective treatment. Previously, we have shown that FAK is overexpressed in pancreatic cancer and plays a key role in cancer cell survival and proliferation. FAK has been shown to interact with growth factor receptors including cMET and IGF-1R. As a novel therapeutic approach, we targeted the protein interaction of FAK with growth factor receptors to block tumor growth, alter signaling pathways and sensitize cells to chemotherapy. We have selected a small molecule compound (INT2-31) that decreases phosphorylation of AKT via disrupting interaction of FAK with cMET and IGF-1R. Our results demonstrate that interaction of a small molecule compound with FAK decreases phosphorylation of FAK Y397 while increasing FAK Y407 phosphorylation, without inhibiting the kinase activity of FAK and dramatically reduces downstream signaling to AKT. Our lead compound, INT2-31, demonstrates significant inhibition of tumor cell growth in two orthotopic models of pancreatic cancer. In addition, INT2-31increases sensitivity to gemcitabine chemotherapy in a direct fresh biopsy xenograft model of pancreatic cancer growth.