In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.

Abstract

PURPOSE:

The pathways underlying basal-like breast cancer are poorly understood, and as yet, there is no approved targeted therapy for this disease. We investigated the role of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors as targeted therapies for basal-like breast cancer.

EXPERIMENTAL DESIGN:

We used pharmacogenomic analysis of a large panel of breast cancer cell lines with detailed accompanying molecular information to identify molecular predictors of response to a potent and selective inhibitor of MEK and also to define molecular mechanisms underlying combined MEK and PI3K targeting in basal-like breast cancer. Hypotheses were confirmed by testing in multiple tumor xenograft models.

RESULTS:

We found that basal-like breast cancer models have an activated RAS-like transcriptional program and show greater sensitivity to a selective inhibitor of MEK compared with models representative of other breast cancer subtypes. We also showed that loss of PTEN is a negative predictor of response to MEK inhibition, that treatment with a selective MEK inhibitor caused up-regulation of PI3K pathway signaling, and that dual blockade of both PI3K and MEK/extracellular signal-regulated kinase signaling synergized to potently impair the growth of basal-like breast cancer models in vitro and in vivo.

CONCLUSIONS:

Our studies suggest that single-agent MEK inhibition is a promising therapeutic modality for basal-like breast cancers with intact PTEN, and also provide a basis for rational combination of MEK and PI3K inhibitors in basal-like cancers with both intact and deleted PTEN.

• Authors: Klaus P Hoeflich, Carol O'Brien, Zachary Boyd, Guy Cavet, Steve Guerrero, Kenneth Jung, Tom Januario, Heidi Savage, Elizabeth Punnoose, Tom Truong, Wei Zhou, Leanne Berry, Lesley Murray, Lukas Amler, Marcia Belvin, Lori S Friedman, Mark R Lackner
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 14 Pg. 4649-64 (Jul 15 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19567590 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Phosphoinositide-3 Kinase Inhibitors
• MAP Kinase Kinase 1
• PTEN Phosphohydrolase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (drug therapy, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cluster Analysis
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Female
• Flow Cytometry
• Gene Expression Profiling
• Humans
• Immunoblotting
• MAP Kinase Kinase 1 (antagonists & inhibitors, genetics, metabolism)
• Mammary Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Mice
• Mice, Inbred Strains
• Mice, Nude
• Mutation
• Oligonucleotide Array Sequence Analysis
• PTEN Phosphohydrolase (genetics, metabolism)
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Xenograft Model Antitumor Assays