Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma.
Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma.
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DOI：
10.1080/15384047.2017.1416937
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发表时间：
2018-04-03
影响因子：
3.6
通讯作者：
Salgia R
中科院分区：
文献类型：
--
作者：
Kanteti R;Mirzapoiazova T;Riehm JJ;Dhanasingh I;Mambetsariev B;Wang J;Kulkarni P;Kaushik G;Seshacharyulu P;Ponnusamy MP;Kindler HL;Nasser MW;Batra SK;Salgia R
粘着斑激酶(FAK)是一种非受体胞浆酪氨酸激酶，在多种正常细胞和肿瘤细胞的生存、增殖、迁移和侵袭等功能中发挥着重要作用。它在胰腺癌(PDAC)和恶性胸膜间皮瘤(MPM)等多种肿瘤中均有高活性和过表达。在这里，我们首先证明了FAK在PDAC和MPM细胞系中都过表达。然后，我们分析了FAK和PYK2的双特异性抑制剂PF-573228和PF-431396以及另一种特异性抑制FAK而不是PYK2的小分子抑制剂VS-6063对PDAC和MPM细胞的生长、运动和侵袭的影响。经PF-573228、PF-431396和VS-6063三种细胞处理后，两种癌细胞的生长和非锚定集落形成均呈剂量依赖性抑制。此外，这些化合物抑制了FAK活性部位Y397的磷酸化，并在功能上诱导了两种细胞株的显著凋亡和细胞周期停滞。利用ECIS(电细胞-底物阻抗传感)系统，我们发现两种PF化合物处理都抑制了PDAC细胞对纤维连接蛋白的黏附和迁移。有趣的是，经PF-573228处理的原生KC(Kras；PdxCre)小鼠的3D肿瘤类器官显示，肿瘤类器官大小显著减小，类器官细胞死亡增加。综上所述，我们的结果表明，FAK是间皮瘤和胰腺癌治疗的重要靶点，值得进一步翻译研究。
The non-receptor cytoplasmic tyrosine kinase, Focal Adhesion Kinase (FAK) is known to play a key role in a variety of normal and cancer cellular functions such as survival, proliferation, migration and invasion. It is highly active and overexpressed in various cancers including Pancreatic Ductal Adenocarcinoma (PDAC) and Malignant Pleural Mesothelioma (MPM). Here, initially, we demonstrate that FAK is overexpressed in both PDAC and MPM cell lines. Then we analyze effects of two small molecule inhibitors PF-573228, and PF-431396, which are dual specificity inhibitors of FAK and proline rich tyrosine kinase 2 (PYK2), as well as VS-6063, another small molecule inhibitor that specifically inhibits FAK but not PYK2 for cell growth, motility and invasion of PDAC and MPM cell lines. Treatment with PF-573228, PF-431396 and VS-6063 cells resulted in a dose-dependent inhibition of growth and anchorage-independent colony formation in both cancer cell lines. Furthermore, these compounds suppressed the phosphorylation of FAK at its active site, Y397, and functionally induced significant apoptosis and cell cycle arrest in both cell lines. Using the ECIS (Electric cell-substrate impedance sensing) system, we found that treatment of both PF compounds suppressed adherence and migration of PDAC cells on fibronectin. Interestingly, 3D-tumor organoids derived from autochthonous KC (Kras;PdxCre) mice treated with PF-573228 revealed a significant decrease in tumor organoid size and increase in organoid cell death. Taken together, our results show that FAK is an important target for mesothelioma and pancreatic cancer therapy that merit further translational studies.
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影响因子：
37.3
作者：
Keleg, Shereen;Buchler, Peter;Ludwig, Roman;Buchler, Markus W;Friess, Helmut
通讯作者：
Friess, Helmut
影响因子：
7.3
作者：
Cance, William G.;Golubovskaya, Vita M.
通讯作者：
Golubovskaya, Vita M.
影响因子：
4.4
作者：
Corsi JM;Rouer E;Girault JA;Enslen H
通讯作者：
Enslen H
影响因子：
4.6
作者：
Kanteti, Rajani;Riehm, Jacob J.;Salgia, Ravi
通讯作者：
Salgia, Ravi
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Ward, Elizabeth
通讯作者：
Ward, Elizabeth