Acquired resistance to everolimus in aromatase inhibitorresistant breast cancer

Mariko Kimura, Toru Hanamura, Kouki Tsuboi, Yosuke Kaneko, Yuri Yamaguchi, Toshifumi Niwa, Kazutaka Narui, Itaru Endo, Shin Ichi Hayashi

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

We previously reported the establishment of several types of long-term estrogendepleted- resistant (EDR) cell lines from MCF-7 breast cancer cells. Type 1 EDR cells exhibited the best-studied mechanism of aromatase inhibitor (AI) resistance, in which estrogen receptor (ER) expression remained positive and PI3K signaling was upregulated. Type 2 EDR cells showed reduced ER activity and upregulated JNK-related signaling. The mTOR inhibitor everolimus reduced growth in cells similar to Type 1 EDR cells. The present study generated everolimus-resistant (EvR) cells from Types 1 and 2 EDR cells following long-term exposure to everolimus in vitro. These EvR cells modeled resistance to AI and everolimus combination therapies following first-line AI treatment failure. In Type 1 EvR cells, everolimus resistance was dependent on MAPK signaling; single agents were not effective, but hormonal therapy combined with a kinase inhibitor effectively reduced cell growth. In Type 2 EvR cells, ER expression remained negative and a JNK inhibitor was ineffective, but a Src inhibitor reduced cell growth. The mechanism of acquired everolimus resistance appears to vary depending on the mechanism of AI resistance. Strategies targeting resistant tumors should be tailored based on the resistance mechanisms, as these mechanisms impact therapeutic efficacy.

Original languageEnglish
Pages (from-to)21468-21477
Number of pages10
JournalOncotarget
Volume9
Issue number30
DOIs
Publication statusPublished - 2018 Apr 20

Keywords

  • Breast cancer
  • Endocrine resistance
  • Estrogen receptor
  • Everolimus
  • MTOR inhibitor

ASJC Scopus subject areas

  • Oncology

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