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Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma

SIMPLE SUMMARY: Both IAP and WEE1 inhibitors have demonstrated therapeutic efficacy in in vitro pre-clinical models of head and neck squamous cell carcinoma (HNSCC). Here, we demonstrate that dual treatment with IAP and WEE1 inhibitors sensitizes both HPV-negative and HPV-positive HNSCC cells to bot...

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Autores principales: Toni, Tiffany, Viswanathan, Ramya, Robbins, Yvette, Gunti, Sreenivasulu, Yang, Xinping, Huynh, Angel, Cheng, Hui, Sowers, Anastasia L., Mitchell, James B., Allen, Clint T., Morgan, Ethan L., Van Waes, Carter
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954698/
https://www.ncbi.nlm.nih.gov/pubmed/36831373
http://dx.doi.org/10.3390/cancers15041029
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author Toni, Tiffany
Viswanathan, Ramya
Robbins, Yvette
Gunti, Sreenivasulu
Yang, Xinping
Huynh, Angel
Cheng, Hui
Sowers, Anastasia L.
Mitchell, James B.
Allen, Clint T.
Morgan, Ethan L.
Van Waes, Carter
author_facet Toni, Tiffany
Viswanathan, Ramya
Robbins, Yvette
Gunti, Sreenivasulu
Yang, Xinping
Huynh, Angel
Cheng, Hui
Sowers, Anastasia L.
Mitchell, James B.
Allen, Clint T.
Morgan, Ethan L.
Van Waes, Carter
author_sort Toni, Tiffany
collection PubMed
description SIMPLE SUMMARY: Both IAP and WEE1 inhibitors have demonstrated therapeutic efficacy in in vitro pre-clinical models of head and neck squamous cell carcinoma (HNSCC). Here, we demonstrate that dual treatment with IAP and WEE1 inhibitors sensitizes both HPV-negative and HPV-positive HNSCC cells to both TNFα-dependent and radiation-associated cell death, demonstrating a potential therapeutic combination to treat these cancers. ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) remains a prevalent diagnosis with current treatment options that include radiotherapy and immune-mediated therapies, in which tumor necrosis factor-α (TNFα) is a key mediator of cytotoxicity. However, HNSCC and other cancers often display TNFα resistance due to activation of the canonical IKK–NFκB/RELA pathway, which is activated by, and induces expression of, cellular inhibitors of apoptosis proteins (cIAPs). Our previous studies have demonstrated that the IAP inhibitor birinapant sensitized HNSCC to TNFα-dependent cell death in vitro and radiotherapy in vivo. Furthermore, we recently demonstrated that the inhibition of the G2/M checkpoint kinase WEE1 also sensitized HNSCC cells to TNFα-dependent cell death, due to the inhibition of the pro-survival IKK-NFκB/RELA complex. Given these observations, we hypothesized that dual-antagonist therapy targeting both IAP and WEE1 proteins may have the potential to synergistically sensitize HNSCC to TNFα-dependent cell death. Using the IAP inhibitor birinapant and the WEE1 inhibitor AZD1775, we show that combination treatment reduced cell viability, proliferation and survival when compared with individual treatment. Furthermore, combination treatment enhanced the sensitivity of HNSCC cells to TNFα-induced cytotoxicity via the induction of apoptosis and DNA damage. Additionally, birinapant and AZD1775 combination treatment decreased cell proliferation and survival in combination with radiotherapy, a critical source of TNFα. These results support further investigation of IAP and WEE1 inhibitor combinations in preclinical and clinical studies in HNSCC.
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spelling pubmed-99546982023-02-25 Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma Toni, Tiffany Viswanathan, Ramya Robbins, Yvette Gunti, Sreenivasulu Yang, Xinping Huynh, Angel Cheng, Hui Sowers, Anastasia L. Mitchell, James B. Allen, Clint T. Morgan, Ethan L. Van Waes, Carter Cancers (Basel) Article SIMPLE SUMMARY: Both IAP and WEE1 inhibitors have demonstrated therapeutic efficacy in in vitro pre-clinical models of head and neck squamous cell carcinoma (HNSCC). Here, we demonstrate that dual treatment with IAP and WEE1 inhibitors sensitizes both HPV-negative and HPV-positive HNSCC cells to both TNFα-dependent and radiation-associated cell death, demonstrating a potential therapeutic combination to treat these cancers. ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) remains a prevalent diagnosis with current treatment options that include radiotherapy and immune-mediated therapies, in which tumor necrosis factor-α (TNFα) is a key mediator of cytotoxicity. However, HNSCC and other cancers often display TNFα resistance due to activation of the canonical IKK–NFκB/RELA pathway, which is activated by, and induces expression of, cellular inhibitors of apoptosis proteins (cIAPs). Our previous studies have demonstrated that the IAP inhibitor birinapant sensitized HNSCC to TNFα-dependent cell death in vitro and radiotherapy in vivo. Furthermore, we recently demonstrated that the inhibition of the G2/M checkpoint kinase WEE1 also sensitized HNSCC cells to TNFα-dependent cell death, due to the inhibition of the pro-survival IKK-NFκB/RELA complex. Given these observations, we hypothesized that dual-antagonist therapy targeting both IAP and WEE1 proteins may have the potential to synergistically sensitize HNSCC to TNFα-dependent cell death. Using the IAP inhibitor birinapant and the WEE1 inhibitor AZD1775, we show that combination treatment reduced cell viability, proliferation and survival when compared with individual treatment. Furthermore, combination treatment enhanced the sensitivity of HNSCC cells to TNFα-induced cytotoxicity via the induction of apoptosis and DNA damage. Additionally, birinapant and AZD1775 combination treatment decreased cell proliferation and survival in combination with radiotherapy, a critical source of TNFα. These results support further investigation of IAP and WEE1 inhibitor combinations in preclinical and clinical studies in HNSCC. MDPI 2023-02-06 /pmc/articles/PMC9954698/ /pubmed/36831373 http://dx.doi.org/10.3390/cancers15041029 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Toni, Tiffany
Viswanathan, Ramya
Robbins, Yvette
Gunti, Sreenivasulu
Yang, Xinping
Huynh, Angel
Cheng, Hui
Sowers, Anastasia L.
Mitchell, James B.
Allen, Clint T.
Morgan, Ethan L.
Van Waes, Carter
Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma
title Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma
title_full Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma
title_fullStr Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma
title_full_unstemmed Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma
title_short Combined Inhibition of IAPs and WEE1 Enhances TNFα- and Radiation-Induced Cell Death in Head and Neck Squamous Carcinoma
title_sort combined inhibition of iaps and wee1 enhances tnfα- and radiation-induced cell death in head and neck squamous carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9954698/
https://www.ncbi.nlm.nih.gov/pubmed/36831373
http://dx.doi.org/10.3390/cancers15041029
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