Combined targeting of mTOR and AKT is an effective strategy for basal-like breast cancer in patient-derived xenograft models.

Abstract

Basal-like breast cancer is an aggressive disease for which targeted therapies are lacking. Recent studies showed that basal-like breast cancer is frequently associated with an increased activity of the phosphatidylinositol 3-kinase (PI3K) pathway, which is critical for cell growth, survival, and angiogenesis. To investigate the therapeutic potential of PI3K pathway inhibition in the treatment of basal-like breast cancer, we evaluated the antitumor effect of the mTOR inhibitor MK-8669 and AKT inhibitor MK-2206 in WU-BC4 and WU-BC5, two patient-derived xenograft models of basal-like breast cancer. Both models showed high levels of AKT phosphorylation and loss of PTEN expression. We observed a synergistic effect of MK-8669 and MK-2206 on tumor growth and cell proliferation in vivo. In addition, MK-8669 and MK-2206 inhibited angiogenesis as determined by CD31 immunohistochemistry. Biomarker studies indicated that treatment with MK-2206 inhibited AKT activation induced by MK-8669. To evaluate the effect of loss of PTEN on tumor cell sensitivity to PI3K pathway inhibition, we knocked down PTEN in WU-BC3, a basal-like breast cancer cell line with intact PTEN. Compared with control (GFP) knockdown, PTEN knockdown led to a more dramatic reduction in cell proliferation and tumor growth inhibition in response to MK-8669 and MK-2206 both in vitro and in vivo. Furthermore, a synergistic effect of these two agents on tumor volume was observed in WU-BC3 with PTEN knockdown. Our results provide a preclinical rationale for future clinical investigation of this combination in basal-like breast cancer with loss of PTEN.

• Authors: Siguang Xu, Shunqiang Li, Zhanfang Guo, Jingqin Luo, Matthew J Ellis, Cynthia X Ma
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 12 Issue 8 Pg. 1665-75 (Aug 2013) ISSN: 1538-8514 [Electronic] United States
• PMID: 23689832 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Protein Kinase Inhibitors
• ridaforolimus
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• PTEN Phosphohydrolase
• Sirolimus

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Breast Neoplasms (drug therapy, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• Enzyme Activation (drug effects)
• Female
• Gene Knockdown Techniques
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Inhibitory Concentration 50
• Neoplasms, Basal Cell (drug therapy, genetics, metabolism, pathology)
• Neovascularization, Pathologic (drug therapy)
• PTEN Phosphohydrolase (genetics)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• Sirolimus (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays