Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.

BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mec...

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Autores: Kaminska, K, Akrap, N, Staaf, J, Alves, CL, Ehinger, A, Ebbesson, A, Hedenfalk, I, Beumers, L, Veerla, S, Harbst, K, Ehmsen, S, Borgquist, S, Borg, A, Perez-Fidalgo, A, Ditzel, HJ, Bosch, A, Honeth, G
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:INCLIVA
Repositorio:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
OAI Identifier:oai:incliva.fundanetsuite.com:p15612
Acceso en línea:https://incliva.portalinvestigacion.com/publicaciones/15612
Access Level:acceso abierto
Palabra clave:Cell cycle inhibitors
Cyclin E2
Endocrine treatment resistance
Fulvestrant
Metastatic breast cancer
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spelling Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.Kaminska, KAkrap, NStaaf, JAlves, CLEhinger, AEbbesson, AHedenfalk, IBeumers, LVeerla, SHarbst, KEhmsen, SBorgquist, SBorg, APerez-Fidalgo, ADitzel, HJBosch, AHoneth, GCell cycle inhibitorsCyclin E2Endocrine treatment resistanceFulvestrantMetastatic breast cancerBACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself. METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant. RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival. CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.BMC2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://incliva.portalinvestigacion.com/publicaciones/15612BREAST CANCER RESEARCHISSN: 14655411ISSNe: 1465542Xreponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVAinstname:INCLIVAInglésinfo:eu-repo/semantics/openAccessoai:incliva.fundanetsuite.com:p156122026-06-07T16:35:31Z
dc.title.none.fl_str_mv Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
title Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
spellingShingle Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
Kaminska, K
Cell cycle inhibitors
Cyclin E2
Endocrine treatment resistance
Fulvestrant
Metastatic breast cancer
title_short Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
title_full Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
title_fullStr Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
title_full_unstemmed Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
title_sort Distinct mechanisms of resistance to fulvestrant treatment dictate level of ER independence and selective response to CDK inhibitors in metastatic breast cancer.
dc.creator.none.fl_str_mv Kaminska, K
Akrap, N
Staaf, J
Alves, CL
Ehinger, A
Ebbesson, A
Hedenfalk, I
Beumers, L
Veerla, S
Harbst, K
Ehmsen, S
Borgquist, S
Borg, A
Perez-Fidalgo, A
Ditzel, HJ
Bosch, A
Honeth, G
author Kaminska, K
author_facet Kaminska, K
Akrap, N
Staaf, J
Alves, CL
Ehinger, A
Ebbesson, A
Hedenfalk, I
Beumers, L
Veerla, S
Harbst, K
Ehmsen, S
Borgquist, S
Borg, A
Perez-Fidalgo, A
Ditzel, HJ
Bosch, A
Honeth, G
author_role author
author2 Akrap, N
Staaf, J
Alves, CL
Ehinger, A
Ebbesson, A
Hedenfalk, I
Beumers, L
Veerla, S
Harbst, K
Ehmsen, S
Borgquist, S
Borg, A
Perez-Fidalgo, A
Ditzel, HJ
Bosch, A
Honeth, G
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Cell cycle inhibitors
Cyclin E2
Endocrine treatment resistance
Fulvestrant
Metastatic breast cancer
topic Cell cycle inhibitors
Cyclin E2
Endocrine treatment resistance
Fulvestrant
Metastatic breast cancer
description BACKGROUND: Resistance to endocrine treatment in metastatic breast cancer is a major clinical challenge. Clinical tools to predict both drug resistance and possible treatment combination approaches to overcome it are lacking. This unmet need is mainly due to the heterogeneity underlying both the mechanisms involved in resistance development and breast cancer itself. METHODS: To study the complexity of the mechanisms involved in the resistance to the selective estrogen receptor degrader (SERD) fulvestrant, we performed comprehensive biomarker analyses using several in vitro models that recapitulate the heterogeneity of developed resistance. We further corroborated our findings in tissue samples from patients treated with fulvestrant. RESULTS: We found that different in vitro models of fulvestrant resistance show variable stability in their phenotypes, which corresponded with distinct genomic alterations. Notably, the studied models presented adaptation at different cell cycle nodes to facilitate progression through the cell cycle and responded differently to CDK inhibitors. Cyclin E2 overexpression was identified as a biomarker of a persistent fulvestrant-resistant phenotype. Comparison of pre- and post-treatment paired tumor biopsies from patients treated with fulvestrant revealed an upregulation of cyclin E2 upon development of resistance. Moreover, overexpression of this cyclin was found to be a prognostic factor determining resistance to fulvestrant and shorter progression-free survival. CONCLUSIONS: These data highlight the complexity of estrogen receptor positive breast cancer and suggest that the development of diverse resistance mechanisms dictate levels of ER independence and potentially cross-resistance to CDK inhibitors.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://incliva.portalinvestigacion.com/publicaciones/15612
url https://incliva.portalinvestigacion.com/publicaciones/15612
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BMC
publisher.none.fl_str_mv BMC
dc.source.none.fl_str_mv BREAST CANCER RESEARCH
ISSN: 14655411
ISSNe: 1465542X
reponame:r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
instname:INCLIVA
instname_str INCLIVA
reponame_str r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
collection r-INCLIVA. Repositorio Institucional de Producción Científica de INCLIVA
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.81155

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