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

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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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.

Original languageEnglish
Article number26
JournalBreast Cancer Research
Volume23
Issue number1
ISSN1465-5411
DOIs
Publication statusPublished - Dec 2021

Keywords

  • Cell cycle inhibitors
  • Cyclin E2
  • Endocrine treatment resistance
  • Fulvestrant
  • Metastatic breast cancer

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