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Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer

David Howard, David James, Jezabel Garcia Parra, Belen Pan Castillo, Jenny Worthington, Nicole Williams, Zoe Bentham, Sophie Colleen Rees, Kerryn Lutchman-Singh, Lewis W. Francis, Paul Rees, Lavinia Margarit, Steve Conlan Orcid Logo, Deya Gonzalez Orcid Logo

Frontiers in Oncology, Volume: 12

Swansea University Authors: David Howard, David James, Jezabel Garcia Parra, Belen Pan Castillo, Zoe Bentham, Steve Conlan Orcid Logo, Deya Gonzalez Orcid Logo

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DOI (Published version): 10.3389/fonc.2022.1014280

Abstract

Background: Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are pre...

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Published in: Frontiers in Oncology
ISSN: 2234-943X
Published: Frontiers Media SA 2022
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URI: https://cronfa.swan.ac.uk/Record/cronfa61957
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fullrecord <?xml version="1.0" encoding="utf-8"?><rfc1807 xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xsd="http://www.w3.org/2001/XMLSchema"><bib-version>v2</bib-version><id>61957</id><entry>2022-11-20</entry><title>Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer</title><swanseaauthors><author><sid>c7c303f6cb3c54c8f7ed2563c1a39759</sid><firstname>David</firstname><surname>Howard</surname><name>David Howard</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>31b39419835be9525450cf1420e63996</sid><ORCID/><firstname>David</firstname><surname>James</surname><name>David James</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>f0342a6c8de90d52996ac44f44908f68</sid><firstname>Jezabel</firstname><surname>Garcia Parra</surname><name>Jezabel Garcia Parra</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>5816ec34b5d7b0ab7c10121d366ce7f1</sid><firstname>Belen</firstname><surname>Pan Castillo</surname><name>Belen Pan Castillo</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>ff600fd9543fafd5feea4f8cb38726e6</sid><firstname>Zoe</firstname><surname>Bentham</surname><name>Zoe Bentham</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>0bb6bd247e32fb4249de62c0013b51cb</sid><ORCID>0000-0002-2562-3461</ORCID><firstname>Steve</firstname><surname>Conlan</surname><name>Steve Conlan</name><active>true</active><ethesisStudent>false</ethesisStudent></author><author><sid>bafdf635eb81280304eedf4b18e65d4e</sid><ORCID>0000-0002-1838-6752</ORCID><firstname>Deya</firstname><surname>Gonzalez</surname><name>Deya Gonzalez</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2022-11-20</date><deptcode>BMS</deptcode><abstract>Background: Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC.Aim: The aim of this study was to evaluate the efficacy of CDKis in platinum resistant OC models and serve as a predictor of potential clinical utility.Methods: The efficacy of CDKi, dinaciclib, was determined in wildtype and platinum resistant cell line pairs representing different OC subtypes. In addition, dinaciclib was evaluated in primary cells isolated from platinum-sensitive and platinum-refractory tumors to increase the clinical relevance of the study.Results and conclusions: Dinaciclib proved highly efficacious in OC cell lines and primary cells, which were over a thousand-fold more sensitive to the CDKi than to cisplatin. Furthermore, cisplatin resistance in these cells did not influence sensitivity to dinaciclib and the two drugs combined additively in both platinum-sensitive and platinum-resistant OC cells suggesting a potential role for pan-CDKis (CDKis targeting multiple CDKs), such as dinaciclib, in the treatment of advanced and platinum-resistant OC.</abstract><type>Journal Article</type><journal>Frontiers in Oncology</journal><volume>12</volume><journalNumber/><paginationStart/><paginationEnd/><publisher>Frontiers Media SA</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2234-943X</issnElectronic><keywords>ovarian cancer, resistance, cyclin dependent kinase inhibitor, dinaciclib, cisplatin, platinum, refractory, flavopiridol</keywords><publishedDay>25</publishedDay><publishedMonth>11</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-11-25</publishedDate><doi>10.3389/fonc.2022.1014280</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><funders>This work was funded by Tenovus Cancer Care (grant no. 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spelling v2 61957 2022-11-20 Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer c7c303f6cb3c54c8f7ed2563c1a39759 David Howard David Howard true false 31b39419835be9525450cf1420e63996 David James David James true false f0342a6c8de90d52996ac44f44908f68 Jezabel Garcia Parra Jezabel Garcia Parra true false 5816ec34b5d7b0ab7c10121d366ce7f1 Belen Pan Castillo Belen Pan Castillo true false ff600fd9543fafd5feea4f8cb38726e6 Zoe Bentham Zoe Bentham true false 0bb6bd247e32fb4249de62c0013b51cb 0000-0002-2562-3461 Steve Conlan Steve Conlan true false bafdf635eb81280304eedf4b18e65d4e 0000-0002-1838-6752 Deya Gonzalez Deya Gonzalez true false 2022-11-20 BMS Background: Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC.Aim: The aim of this study was to evaluate the efficacy of CDKis in platinum resistant OC models and serve as a predictor of potential clinical utility.Methods: The efficacy of CDKi, dinaciclib, was determined in wildtype and platinum resistant cell line pairs representing different OC subtypes. In addition, dinaciclib was evaluated in primary cells isolated from platinum-sensitive and platinum-refractory tumors to increase the clinical relevance of the study.Results and conclusions: Dinaciclib proved highly efficacious in OC cell lines and primary cells, which were over a thousand-fold more sensitive to the CDKi than to cisplatin. Furthermore, cisplatin resistance in these cells did not influence sensitivity to dinaciclib and the two drugs combined additively in both platinum-sensitive and platinum-resistant OC cells suggesting a potential role for pan-CDKis (CDKis targeting multiple CDKs), such as dinaciclib, in the treatment of advanced and platinum-resistant OC. Journal Article Frontiers in Oncology 12 Frontiers Media SA 2234-943X ovarian cancer, resistance, cyclin dependent kinase inhibitor, dinaciclib, cisplatin, platinum, refractory, flavopiridol 25 11 2022 2022-11-25 10.3389/fonc.2022.1014280 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University This work was funded by Tenovus Cancer Care (grant no. PhD2015/L35), the Life Science National Research Network in Drug Discovery (2016/BPC) and Welsh Government ERDF SMART Expertise 2014-2020 West Wales and the Valleys (2017/COL/001 and 2017/COL/004). 2023-09-13T14:56:14.5565946 2022-11-20T15:31:52.3251634 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine David Howard 1 David James 2 Jezabel Garcia Parra 3 Belen Pan Castillo 4 Jenny Worthington 5 Nicole Williams 6 Zoe Bentham 7 Sophie Colleen Rees 8 Kerryn Lutchman-Singh 9 Lewis W. Francis 10 Paul Rees 11 Lavinia Margarit 12 Steve Conlan 0000-0002-2562-3461 13 Deya Gonzalez 0000-0002-1838-6752 14 61957__26097__64130a82741a418a9e5a4f3139899e9a.pdf 61957.pdf 2022-12-16T10:09:15.6664184 Output 6996277 application/pdf Version of Record true © 2022 Howard, James, Garcia-Parra, Pan-Castillo, Worthington, Williams, Coombes, Rees, Lutchman-Singh, Francis, Rees, Margarit, Conlan and Gonzalez. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). true eng http://creativecommons.org/licenses/by/4.0/
title Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
spellingShingle Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
David Howard
David James
Jezabel Garcia Parra
Belen Pan Castillo
Zoe Bentham
Steve Conlan
Deya Gonzalez
title_short Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
title_full Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
title_fullStr Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
title_full_unstemmed Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
title_sort Dinaciclib as an effective pan-cyclin dependent kinase inhibitor in platinum resistant ovarian cancer
author_id_str_mv c7c303f6cb3c54c8f7ed2563c1a39759
31b39419835be9525450cf1420e63996
f0342a6c8de90d52996ac44f44908f68
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ff600fd9543fafd5feea4f8cb38726e6
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author_id_fullname_str_mv c7c303f6cb3c54c8f7ed2563c1a39759_***_David Howard
31b39419835be9525450cf1420e63996_***_David James
f0342a6c8de90d52996ac44f44908f68_***_Jezabel Garcia Parra
5816ec34b5d7b0ab7c10121d366ce7f1_***_Belen Pan Castillo
ff600fd9543fafd5feea4f8cb38726e6_***_Zoe Bentham
0bb6bd247e32fb4249de62c0013b51cb_***_Steve Conlan
bafdf635eb81280304eedf4b18e65d4e_***_Deya Gonzalez
author David Howard
David James
Jezabel Garcia Parra
Belen Pan Castillo
Zoe Bentham
Steve Conlan
Deya Gonzalez
author2 David Howard
David James
Jezabel Garcia Parra
Belen Pan Castillo
Jenny Worthington
Nicole Williams
Zoe Bentham
Sophie Colleen Rees
Kerryn Lutchman-Singh
Lewis W. Francis
Paul Rees
Lavinia Margarit
Steve Conlan
Deya Gonzalez
format Journal article
container_title Frontiers in Oncology
container_volume 12
publishDate 2022
institution Swansea University
issn 2234-943X
doi_str_mv 10.3389/fonc.2022.1014280
publisher Frontiers Media SA
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Background: Ovarian cancer (OC) is amongst the most lethal of common cancers in women. Lacking in specific symptoms in the early stages, OC is predominantly diagnosed late when the disease has undergone metastatic spread and chemotherapy is relied on to prolong life. Platinum-based therapies are preferred and although many tumors respond initially, the emergence of platinum-resistance occurs in the majority of cases after which prognosis is very poor. Upregulation of DNA damage pathways is a common feature of platinum resistance in OC with cyclin dependent kinases (CDKs) serving as key regulators of this process and suggesting that CDK inhibitors (CDKis) could be effective tools in the treatment of platinum resistant and refractory OC.Aim: The aim of this study was to evaluate the efficacy of CDKis in platinum resistant OC models and serve as a predictor of potential clinical utility.Methods: The efficacy of CDKi, dinaciclib, was determined in wildtype and platinum resistant cell line pairs representing different OC subtypes. In addition, dinaciclib was evaluated in primary cells isolated from platinum-sensitive and platinum-refractory tumors to increase the clinical relevance of the study.Results and conclusions: Dinaciclib proved highly efficacious in OC cell lines and primary cells, which were over a thousand-fold more sensitive to the CDKi than to cisplatin. Furthermore, cisplatin resistance in these cells did not influence sensitivity to dinaciclib and the two drugs combined additively in both platinum-sensitive and platinum-resistant OC cells suggesting a potential role for pan-CDKis (CDKis targeting multiple CDKs), such as dinaciclib, in the treatment of advanced and platinum-resistant OC.
published_date 2022-11-25T14:56:16Z
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