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CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues

The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint act...

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Autores principales: Tat, John, Loriot, Céline, Henze, Martha, Spruck, Charles, Felding, Brunhilde H., Reed, Steven I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777741/
https://www.ncbi.nlm.nih.gov/pubmed/29383129
http://dx.doi.org/10.18632/oncotarget.22931
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author Tat, John
Loriot, Céline
Henze, Martha
Spruck, Charles
Felding, Brunhilde H.
Reed, Steven I.
author_facet Tat, John
Loriot, Céline
Henze, Martha
Spruck, Charles
Felding, Brunhilde H.
Reed, Steven I.
author_sort Tat, John
collection PubMed
description The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach.
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spelling pubmed-57777412018-01-30 CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues Tat, John Loriot, Céline Henze, Martha Spruck, Charles Felding, Brunhilde H. Reed, Steven I. Oncotarget Research Paper The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach. Impact Journals LLC 2017-12-04 /pmc/articles/PMC5777741/ /pubmed/29383129 http://dx.doi.org/10.18632/oncotarget.22931 Text en Copyright: © 2017 Tat et al. http://creativecommons.org/licenses/by/3.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Research Paper
Tat, John
Loriot, Céline
Henze, Martha
Spruck, Charles
Felding, Brunhilde H.
Reed, Steven I.
CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues
title CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues
title_full CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues
title_fullStr CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues
title_full_unstemmed CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues
title_short CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues
title_sort cks protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777741/
https://www.ncbi.nlm.nih.gov/pubmed/29383129
http://dx.doi.org/10.18632/oncotarget.22931
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