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FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways

Focal adhesion kinase (FAK) is highly expressed in a variety of human cancers and is a target for cancer therapy. Since FAK kinase inhibitors only block the kinase activity of FAK, they are not highly effective in clinical trials. FAK also functions as a scaffold protein in a kinase-independent path...

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Autores principales: Huo, Xueyun, Zhang, Wenjing, Zhao, Guannan, Chen, Zhenwen, Dong, Peixin, Watari, Hidemichi, Narayanan, Ramesh, Tillmanns, Todd D., Pfeffer, Lawrence M., Yue, Junming
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095959/
https://www.ncbi.nlm.nih.gov/pubmed/35574330
http://dx.doi.org/10.3389/fonc.2022.851065
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author Huo, Xueyun
Zhang, Wenjing
Zhao, Guannan
Chen, Zhenwen
Dong, Peixin
Watari, Hidemichi
Narayanan, Ramesh
Tillmanns, Todd D.
Pfeffer, Lawrence M.
Yue, Junming
author_facet Huo, Xueyun
Zhang, Wenjing
Zhao, Guannan
Chen, Zhenwen
Dong, Peixin
Watari, Hidemichi
Narayanan, Ramesh
Tillmanns, Todd D.
Pfeffer, Lawrence M.
Yue, Junming
author_sort Huo, Xueyun
collection PubMed
description Focal adhesion kinase (FAK) is highly expressed in a variety of human cancers and is a target for cancer therapy. Since FAK kinase inhibitors only block the kinase activity of FAK, they are not highly effective in clinical trials. FAK also functions as a scaffold protein in a kinase-independent pathway. To effectively target FAK, it is required to block both FAK kinase-dependent and FAK-independent pathways. Thus, we tested a new generation drug FAK PROTAC for ovarian cancer therapy, which blocks both kinase and scaffold activity. We tested the efficacy of FAK PROTAC and its parent kinase inhibitor (VS-6063) in ovarian cancer cell lines in vitro by performing cell functional assays including cell proliferation, migration, invasion. We also tested in vivo activity in orthotopic ovarian cancer mouse models. In addition, we assessed whether FAK PROTAC disrupts kinase-dependent and kinase-independent pathways. We demonstrated that FAK PROTAC is highly effective as compared to its parent FAK kinase inhibitor VS-6063 in inhibiting cell proliferation, survival, migration, and invasion. FAK PROTAC not only inhibits the FAK kinase activity but also FAK scaffold function by disrupting the interaction between FAK and its interaction protein ASAP1. We further showed that FAK PROTAC effectively inhibits ovarian tumor growth and metastasis. Taken together, FAK PROTAC inhibits both FAK kinase activity and its scaffold protein activity by disrupting the interaction between FAK and ASAP1 and is highly effective in inhibiting ovarian tumor growth and metastasis.
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spelling pubmed-90959592022-05-13 FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways Huo, Xueyun Zhang, Wenjing Zhao, Guannan Chen, Zhenwen Dong, Peixin Watari, Hidemichi Narayanan, Ramesh Tillmanns, Todd D. Pfeffer, Lawrence M. Yue, Junming Front Oncol Oncology Focal adhesion kinase (FAK) is highly expressed in a variety of human cancers and is a target for cancer therapy. Since FAK kinase inhibitors only block the kinase activity of FAK, they are not highly effective in clinical trials. FAK also functions as a scaffold protein in a kinase-independent pathway. To effectively target FAK, it is required to block both FAK kinase-dependent and FAK-independent pathways. Thus, we tested a new generation drug FAK PROTAC for ovarian cancer therapy, which blocks both kinase and scaffold activity. We tested the efficacy of FAK PROTAC and its parent kinase inhibitor (VS-6063) in ovarian cancer cell lines in vitro by performing cell functional assays including cell proliferation, migration, invasion. We also tested in vivo activity in orthotopic ovarian cancer mouse models. In addition, we assessed whether FAK PROTAC disrupts kinase-dependent and kinase-independent pathways. We demonstrated that FAK PROTAC is highly effective as compared to its parent FAK kinase inhibitor VS-6063 in inhibiting cell proliferation, survival, migration, and invasion. FAK PROTAC not only inhibits the FAK kinase activity but also FAK scaffold function by disrupting the interaction between FAK and its interaction protein ASAP1. We further showed that FAK PROTAC effectively inhibits ovarian tumor growth and metastasis. Taken together, FAK PROTAC inhibits both FAK kinase activity and its scaffold protein activity by disrupting the interaction between FAK and ASAP1 and is highly effective in inhibiting ovarian tumor growth and metastasis. Frontiers Media S.A. 2022-04-28 /pmc/articles/PMC9095959/ /pubmed/35574330 http://dx.doi.org/10.3389/fonc.2022.851065 Text en Copyright © 2022 Huo, Zhang, Zhao, Chen, Dong, Watari, Narayanan, Tillmanns, Pfeffer and Yue https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Huo, Xueyun
Zhang, Wenjing
Zhao, Guannan
Chen, Zhenwen
Dong, Peixin
Watari, Hidemichi
Narayanan, Ramesh
Tillmanns, Todd D.
Pfeffer, Lawrence M.
Yue, Junming
FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways
title FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways
title_full FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways
title_fullStr FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways
title_full_unstemmed FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways
title_short FAK PROTAC Inhibits Ovarian Tumor Growth and Metastasis by Disrupting Kinase Dependent and Independent Pathways
title_sort fak protac inhibits ovarian tumor growth and metastasis by disrupting kinase dependent and independent pathways
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9095959/
https://www.ncbi.nlm.nih.gov/pubmed/35574330
http://dx.doi.org/10.3389/fonc.2022.851065
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