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

Kamila Kaminska, Nina Akrap, Johan Staaf, Carla L. Alves, Anna Ehinger, Anna Ebbesson, Ingrid Hedenfalk, Lukas Beumers, Srinivas Veerla, Katja Harbst, Sidse Ehmsen, Signe Borgquist, Åke Borg, Alejandro Pérez-Fidalgo, Henrik J. Ditzel, Ana Bosch*, Gabriella Honeth

*Kontaktforfatter for dette arbejde

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummer26
TidsskriftBreast Cancer Research
Vol/bind23
Udgave nummer1
ISSN1465-5411
DOI
StatusUdgivet - dec. 2021

Bibliografisk note

Funding Information:
The study received funding from Mrs. Berta Kamprad’s Cancer Foundation, the Crafoord Foundation, Gunnar Nilsson Cancer Foundation, Swedish Breast Cancer Group, the Royal Physiographic Society of Lund, Percy Falk’s Foundation, Skåne University Hospital Foundations and Donations, and the ISREC Foundation thanks to a donation from the Biltema Foundation. AB holds a Governmental Funding for Young Clinical Researchers within the National Health Service grant (ALF) 2017–2020. The funding bodies had no role in the design, data analysis, or manuscript preparation/publication. Open Access funding provided by Lund University.

Funding Information:
The authors would like to acknowledge the Center for Translational Genomics, Lund University and Clinical Genomics Lund, SciLifeLab, for support with gene expression analyses.

Publisher Copyright:
© 2021, The Author(s).

Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.

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