Decreased ER dependency after acquired resistance to CDK4/6 inhibitors

Masafumi Iida, Daichi Toyosawa, Misato Nakamura, Kouki Tsuboi, Emi Tokuda, Toshifumi Niwa, Takanori Ishida, Shin ichi Hayashi

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors represent a significant advancement in the treatment of estrogen receptor (ER)-positive human epidermal growth factor receptor 2-negative advanced breast cancer. However, mechanisms of alterations after acquired resistance to CDK4/6 inhibitors and the optimal treatment options are still not established. Methods: Abemaciclib-resistant cell lines were established from the models of estrogen deprivation-resistant cell lines which retained ER expression and activated ER function derived from MCF-7 breast cancer cell lines. Ribocilib-resistant cell lines were established in the same method as previously reported. Results: Both abemaciclib- and ribociclib-resistant cell lines showed decreased ER expression. ER transcriptional activity was maintained in these cell lines; however, the sensitivity to 4-hydroxytamoxifen and fulvestrant was almost completely lost. These cell lines did not exhibit any ERα gene mutation. Abemaciclib-resistant cell lines demonstrated low sensitivity to other CDK4/6 inhibitors; sensitivities to PI3K inhibitor, mTOR inhibitor, and chemotherapeutic drugs were maintained. Conclusions: Dependence on ER signaling appears to decrease after the development of acquired resistance to CDK4/6 inhibitors. Further, CDK4/6 inhibitor-resistant cells acquired cross-resistance to other CDK4/6 inhibitors, PI3K/Akt/mTOR inhibitor therapy and chemotherapeutic drugs might serve as optimal treatment options for such breast cancers.

Original languageEnglish
Pages (from-to)963-972
Number of pages10
JournalBreast Cancer
Volume27
Issue number5
DOIs
Publication statusPublished - 2020 Sep 1

Keywords

  • Abemaciclib
  • Breast cancer
  • CDK4/6 inhibitor
  • Estrogen receptor
  • Resistance

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Pharmacology (medical)

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