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

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 aromatase inhibitor 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 alpha 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.

• Authors: M Beeram, Q-T N Tan, R R Tekmal, D Russell, A Middleton, L A DeGraffenried
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 18 Issue 8 Pg. 1323-8 (Aug 2007) ISSN: 0923-7534 [Print] England
• PMID: 17693645 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Hormonal
• Aromatase Inhibitors
• Nitriles
• Triazoles
• Fulvestrant
• Estradiol
• Letrozole
• Everolimus
• Protein Kinases
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Antineoplastic Agents, Hormonal (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Aromatase Inhibitors (pharmacology)
• Blotting, Western
• Breast Neoplasms (drug therapy)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm (physiology)
• Estradiol (analogs & derivatives, pharmacology)
• Everolimus
• Female
• Flow Cytometry
• Fulvestrant
• Humans
• Letrozole
• Nitriles (pharmacology)
• Protein Kinases (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Sirolimus (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases
• Triazoles (pharmacology)