Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling

M. Beeram, Q. T.N. Tan, R. R. Tekmal, D. Russell, A. Middleton, L. A. deGraffenried

Research output: Contribution to journalArticle

147 Scopus citations

Abstract

Background: Resistance to endocrine therapy is a major impediment in breast cancer therapeutics. The Phosphatidylinositol-3-OH kinase (PI3K)/ Protein kinase B (Akt/PKB) kinase signaling pathway has been implicated in altering breast cancer response to multiple therapies. How Akt modulates response is an area of significant clinical relevance. Methods: We have used an in vitro model to discern the effects of robust Akt activity on breast cancer cellular response to endocrine therapies. Results: High levels of Akt activity confer resistance to the aromataseinhibitor Letrozole (Let) and the selective estrogen receptor (ER) down-regulator Fulvestrant (ICI). Akt-induced resistance is not due to failure of these endocrine agents to inhibit estrogen receptor α activity. Instead, resistance is characterized by altered cell cycle and apoptotic response. Cotreatment with low concentrations of the mTOR inhibitor RAD-001 and either Let or ICI restores response of the resistant cells to levels observed in the responsive cells treated with either Let or ICI as a single agent. Conclusions: Our preliminary findings in experiments with RAD-001 indicate that cotreatment with mTOR inhibitors and either Let or ICI reverses the Akt-mediated resistance and restores responsiveness to antiestrogens. Concurrent ER and mTOR inhibition is therefore an effective strategy to overcome growth factor-induced resistance and bears significant implications for optimal clinical development of these agents in breast cancer treatment.

Original languageEnglish (US)
Pages (from-to)1323-1328
Number of pages6
JournalAnnals of Oncology
Volume18
Issue number8
DOIs
StatePublished - Aug 1 2007

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Keywords

  • Akt
  • Breast cancer
  • Endocrine therapy
  • mTOR

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

Beeram, M., Tan, Q. T. N., Tekmal, R. R., Russell, D., Middleton, A., & deGraffenried, L. A. (2007). Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling. Annals of Oncology, 18(8), 1323-1328. https://doi.org/10.1093/annonc/mdm170