Acquired resistance to everolimus in aromatase inhibitor-resistant breast cancer

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Mariko Kimura1,2,3, Toru Hanamura1,4, Kouki Tsuboi1

  • 1Department of Molecular and Functional Dynamics, Tohoku University Graduate School of Medicine, Sendai, Japan.

Oncotarget
|May 17, 2018
PubMed

Insights

Estrogen-depleted-resistant (EDR) breast cancer cells developed resistance to everolimus. Tailoring combination therapies based on specific resistance mechanisms is crucial for treating resistant tumors effectively.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Established estrogen-depleted-resistant (EDR) cell lines from MCF-7 breast cancer cells, categorizing them into Type 1 (ER-positive, PI3K upregulated) and Type 2 (ER-negative, JNK upregulated).
  • Noted that everolimus, an mTOR inhibitor, reduced growth in Type 1 EDR cells.

Purpose of the Study:

  • To generate and characterize everolimus-resistant (EvR) cell lines from both Type 1 and Type 2 EDR cells.
  • To investigate resistance mechanisms to combination therapies involving aromatase inhibitors (AIs) and everolimus after AI treatment failure.

Main Methods:

  • Long-term in vitro exposure of Type 1 and Type 2 EDR cells to everolimus to generate EvR cell lines.
  • Assessed the efficacy of single agents versus combination therapies (hormonal therapy + kinase inhibitor, JNK inhibitor, or Src inhibitor) in EvR cells.

Main Results:

  • Type 1 EvR cells exhibited everolimus resistance mediated by MAPK signaling; combination therapy with hormonal agents and kinase inhibitors was effective.
  • Type 2 EvR cells showed resistance independent of JNK signaling, but a Src inhibitor effectively reduced cell growth.
  • Demonstrated that acquired everolimus resistance mechanisms differ based on the initial AI resistance mechanism.

Conclusions:

  • Acquired resistance to everolimus in breast cancer is heterogeneous and depends on the underlying AI resistance mechanism.
  • Therapeutic strategies for resistant breast cancer should be personalized based on identified resistance pathways for optimal efficacy.
Keywords:
breast cancerendocrine resistanceestrogen receptoreverolimusmTOR inhibitor

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