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

Content Provider	Springer Nature : BioMed Central
Author	Kaminska, Kamila Akrap, Nina Staaf, Johan Alves, Carla L. Ehinger, Anna Ebbesson, Anna Hedenfalk, Ingrid Beumers, Lukas Veerla, Srinivas Harbst, Katja Ehmsen, Sidse Borgquist, Signe Borg, Åke Pérez-Fidalgo, Alejandro Ditzel, Henrik J. Bosch, Ana Honeth, Gabriella
Abstract	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.
Related Links	https://breast-cancer-research.biomedcentral.com/counter/pdf/10.1186/s13058-021-01402-1.pdf
Ending Page	18
Page Count	18
Starting Page	1
File Format	HTM / HTML
DOI	10.1186/s13058-021-01402-1
Journal	Breast Cancer Research
Issue Number	1
Volume Number	23
Language	English
Publisher	BioMed Central
Publisher Date	2021-02-18
Access Restriction	Open
Subject Keyword	Cancer Research Oncology Surgical Oncology Metastatic breast cancer Endocrine treatment resistance Cell cycle inhibitors Fulvestrant Cyclin E2
Content Type	Text
Resource Type	Article
Subject	Cancer Research Oncology
Journal Impact Factor	6.1/2023
5-Year Journal Impact Factor	7.1/2023

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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