TY - JOUR
T1 - Focal adhesion kinase a potential therapeutic target for pancreatic cancer and malignant pleural mesothelioma
AU - Kanteti, Rajani
AU - Mirzapoiazova, Tamara
AU - Riehm, Jacob J.
AU - Dhanasingh, Immanuel
AU - Mambetsariev, Bolot
AU - Wang, Jiale
AU - Kulkarni, Prakash
AU - Kaushik, Garima
AU - Seshacharyulu, Parthasarathy
AU - Ponnusamy, Moorthy P.
AU - Kindler, Hedy L.
AU - Nasser, Mohd W.
AU - Batra, Surinder K.
AU - Salgia, Ravi
N1 - Funding Information:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award number P30CA033572. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Publisher Copyright:
© 2018 The Author(s). Published with license by Taylor & Francis Group, LLC © 2018, © Rajani Kanteti, Tamara Mirzapoiazova, Jacob J. Riehm, Immanuel Dhanasingh, Bolot Mambetsariev, Jiale Wang, Prakash Kulkarni, Garima Kaushik, Parthasarathy Seshacharyulu, Moorthy P. Ponnusamy, Hedy L. Kindler, Mohd W. Nasser, Surinder K. Batra and Ravi Salgia.
PY - 2018/4/3
Y1 - 2018/4/3
N2 - 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.
AB - 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.
KW - FAK
KW - PF-431396
KW - PF-573228
KW - VS-6063
KW - mesothelioma
KW - pancreatic cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85042362150&partnerID=8YFLogxK
U2 - 10.1080/15384047.2017.1416937
DO - 10.1080/15384047.2017.1416937
M3 - Article
C2 - 29303405
AN - SCOPUS:85042362150
SN - 1538-4047
VL - 19
SP - 316
EP - 327
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 4
ER -