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Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma

Clear cell renal cell carcinoma (CC-RCC) remains one of the most deadly forms of kidney cancer despite recent advancements in targeted therapeutics, including tyrosine kinase and immune checkpoint inhibitors. Unfortunately, these therapies have not been able to show better than a 16% complete respon...

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Autores principales: Nelson, Luke J, Castro, Kyleen E, Xu, Binzhi, Li, Junyi, Dinh, Nguyen B, Thompson, Jordan M, Woytash, Jordan, Kipp, Kevin R, Razorenova, Olga V
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037521/
https://www.ncbi.nlm.nih.gov/pubmed/35240916
http://dx.doi.org/10.1080/15384101.2022.2041783
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author Nelson, Luke J
Castro, Kyleen E
Xu, Binzhi
Li, Junyi
Dinh, Nguyen B
Thompson, Jordan M
Woytash, Jordan
Kipp, Kevin R
Razorenova, Olga V
author_facet Nelson, Luke J
Castro, Kyleen E
Xu, Binzhi
Li, Junyi
Dinh, Nguyen B
Thompson, Jordan M
Woytash, Jordan
Kipp, Kevin R
Razorenova, Olga V
author_sort Nelson, Luke J
collection PubMed
description Clear cell renal cell carcinoma (CC-RCC) remains one of the most deadly forms of kidney cancer despite recent advancements in targeted therapeutics, including tyrosine kinase and immune checkpoint inhibitors. Unfortunately, these therapies have not been able to show better than a 16% complete response rate. In this study we evaluated a cyclin-dependent kinase inhibitor, Dinaciclib, as a potential new targeted therapeutic for CC-RCC. In vitro, Dinaciclib showed anti-proliferative and pro-apoptotic effects on CC-RCC cell lines in Cell Titer Glo, Crystal Violet, FACS-based cell cycle analysis, and TUNEL assays. Additionally, these responses were accompanied by a reduction in phospho-Rb and pro-survival MCL-1 cell signaling responses, as well as the induction of caspase 3 and PARP cleavage. In vivo, Dinaciclib efficiently inhibited primary tumor growth in an orthotopic, patient-derived xenograft-based CC-RCC mouse model. Importantly, Dinaciclib targeted both CD105(+) cancer stem cells (CSCs) and CD105(−) non-CSCs in vivo. Moreover, normal cell lines, as well as a CC-RCC cell line with re-expressed von-Hippel Lindau (VHL) tumor suppressor gene, were protected from Dinaciclib-induced cytotoxicity when not actively dividing, indicating an effective therapeutic window due to synthetic lethality of Dinaciclib treatment with VHL loss. Thus, Dinaciclib represents a novel potential therapeutic for CC-RCC.
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spelling pubmed-90375212022-04-26 Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma Nelson, Luke J Castro, Kyleen E Xu, Binzhi Li, Junyi Dinh, Nguyen B Thompson, Jordan M Woytash, Jordan Kipp, Kevin R Razorenova, Olga V Cell Cycle Research Paper Clear cell renal cell carcinoma (CC-RCC) remains one of the most deadly forms of kidney cancer despite recent advancements in targeted therapeutics, including tyrosine kinase and immune checkpoint inhibitors. Unfortunately, these therapies have not been able to show better than a 16% complete response rate. In this study we evaluated a cyclin-dependent kinase inhibitor, Dinaciclib, as a potential new targeted therapeutic for CC-RCC. In vitro, Dinaciclib showed anti-proliferative and pro-apoptotic effects on CC-RCC cell lines in Cell Titer Glo, Crystal Violet, FACS-based cell cycle analysis, and TUNEL assays. Additionally, these responses were accompanied by a reduction in phospho-Rb and pro-survival MCL-1 cell signaling responses, as well as the induction of caspase 3 and PARP cleavage. In vivo, Dinaciclib efficiently inhibited primary tumor growth in an orthotopic, patient-derived xenograft-based CC-RCC mouse model. Importantly, Dinaciclib targeted both CD105(+) cancer stem cells (CSCs) and CD105(−) non-CSCs in vivo. Moreover, normal cell lines, as well as a CC-RCC cell line with re-expressed von-Hippel Lindau (VHL) tumor suppressor gene, were protected from Dinaciclib-induced cytotoxicity when not actively dividing, indicating an effective therapeutic window due to synthetic lethality of Dinaciclib treatment with VHL loss. Thus, Dinaciclib represents a novel potential therapeutic for CC-RCC. Taylor & Francis 2022-03-04 /pmc/articles/PMC9037521/ /pubmed/35240916 http://dx.doi.org/10.1080/15384101.2022.2041783 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Research Paper
Nelson, Luke J
Castro, Kyleen E
Xu, Binzhi
Li, Junyi
Dinh, Nguyen B
Thompson, Jordan M
Woytash, Jordan
Kipp, Kevin R
Razorenova, Olga V
Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma
title Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma
title_full Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma
title_fullStr Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma
title_full_unstemmed Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma
title_short Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL-deficiency allows for selective targeting of clear cell renal cell carcinoma
title_sort synthetic lethality of cyclin-dependent kinase inhibitor dinaciclib with vhl-deficiency allows for selective targeting of clear cell renal cell carcinoma
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037521/
https://www.ncbi.nlm.nih.gov/pubmed/35240916
http://dx.doi.org/10.1080/15384101.2022.2041783
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