IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK

Abstract Head and neck cancer is the sixth most common cancer worldwide with a 5-year survival of only 65%. Targeting compensatory signaling pathways may improve therapeutic responses and combat resistance. Utilizing reverse phase protein arrays (RPPA) to assess the proteome and explore mechanisms o...

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Autores principales:	Christine E. Lehman, Adam Spencer, Sarah Hall, Jeremy J. P. Shaw, Julia Wulfkuhle, Emanuel F. Petricoin, Stefan Bekiranov, Mark J. Jameson, Daniel Gioeli
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3b347bf831e74651bf20811b8511fc1e
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spelling	oai:doaj.org-article:3b347bf831e74651bf20811b8511fc1e2021-12-02T14:49:24ZIGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK10.1038/s41598-021-90289-12045-2322https://doaj.org/article/3b347bf831e74651bf20811b8511fc1e2021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90289-1https://doaj.org/toc/2045-2322Abstract Head and neck cancer is the sixth most common cancer worldwide with a 5-year survival of only 65%. Targeting compensatory signaling pathways may improve therapeutic responses and combat resistance. Utilizing reverse phase protein arrays (RPPA) to assess the proteome and explore mechanisms of synergistic growth inhibition in HNSCC cell lines treated with IGF1R and Src inhibitors, BMS754807 and dasatinib, respectively, we identified focal adhesion signaling as a critical node. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation were decreased as early as 15 min after treatment, and treatment with a FAK inhibitor, PF-562,271, was sufficient to decrease viability in vitro. Treatment of 3D spheroids demonstrated robust cytotoxicity suggesting that the combination of BMS754807 and dasatinib is effective in multiple experimental models. Furthermore, treatment with BMS754807 and dasatinib significantly decreased cell motility, migration, and invasion in multiple HNSCC cell lines. Most strikingly, treatment with BMS754807 and dasatinib, or a FAK inhibitor alone, significantly increased cleaved-PARP in human ex-vivo HNSCC patient tissues demonstrating a potential clinical utility for targeting FAK or the combined targeting of the IGF1R with Src. This ex-vivo result further confirms FAK as a vital signaling node of this combinatorial treatment and demonstrates therapeutic potential for targeting FAK in HNSCC patients.Christine E. LehmanAdam SpencerSarah HallJeremy J. P. ShawJulia WulfkuhleEmanuel F. PetricoinStefan BekiranovMark J. JamesonDaniel GioeliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Christine E. Lehman Adam Spencer Sarah Hall Jeremy J. P. Shaw Julia Wulfkuhle Emanuel F. Petricoin Stefan Bekiranov Mark J. Jameson Daniel Gioeli IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK
description	Abstract Head and neck cancer is the sixth most common cancer worldwide with a 5-year survival of only 65%. Targeting compensatory signaling pathways may improve therapeutic responses and combat resistance. Utilizing reverse phase protein arrays (RPPA) to assess the proteome and explore mechanisms of synergistic growth inhibition in HNSCC cell lines treated with IGF1R and Src inhibitors, BMS754807 and dasatinib, respectively, we identified focal adhesion signaling as a critical node. Focal Adhesion Kinase (FAK) and Paxillin phosphorylation were decreased as early as 15 min after treatment, and treatment with a FAK inhibitor, PF-562,271, was sufficient to decrease viability in vitro. Treatment of 3D spheroids demonstrated robust cytotoxicity suggesting that the combination of BMS754807 and dasatinib is effective in multiple experimental models. Furthermore, treatment with BMS754807 and dasatinib significantly decreased cell motility, migration, and invasion in multiple HNSCC cell lines. Most strikingly, treatment with BMS754807 and dasatinib, or a FAK inhibitor alone, significantly increased cleaved-PARP in human ex-vivo HNSCC patient tissues demonstrating a potential clinical utility for targeting FAK or the combined targeting of the IGF1R with Src. This ex-vivo result further confirms FAK as a vital signaling node of this combinatorial treatment and demonstrates therapeutic potential for targeting FAK in HNSCC patients.
format	article
author	Christine E. Lehman Adam Spencer Sarah Hall Jeremy J. P. Shaw Julia Wulfkuhle Emanuel F. Petricoin Stefan Bekiranov Mark J. Jameson Daniel Gioeli
author_facet	Christine E. Lehman Adam Spencer Sarah Hall Jeremy J. P. Shaw Julia Wulfkuhle Emanuel F. Petricoin Stefan Bekiranov Mark J. Jameson Daniel Gioeli
author_sort	Christine E. Lehman
title	IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK
title_short	IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK
title_full	IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK
title_fullStr	IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK
title_full_unstemmed	IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK
title_sort	igf1r and src inhibition induce synergistic cytotoxicity in hnscc through inhibition of fak
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3b347bf831e74651bf20811b8511fc1e
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IGF1R and Src inhibition induce synergistic cytotoxicity in HNSCC through inhibition of FAK

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