Abstract
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. 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. 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. 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.
Highlights
The pathways underlying basal-like breast cancer are poorly understood, and as yet, there is no approved targeted therapy for this disease
We find that basal-like breast cancer models are sensitive in vitro and in vivo to the inhibitory effects of mitogenactivated protein kinase kinase (MEK) inhibition relative to luminal and HER2-amplified tumors and identify the tumor suppressor PTEN as a negative predictor factor for response to MEK inhibition.We find that a combination of MEK and phosphatidylinositol 3-kinase inhibitors results in enhanced efficacy in both PTEN wild-type and PTEN-null basal-like tumors and provide a mechanistic explanation for this observation
We used quantitative reverse-phase protein microarrays to assess levels of pAkt (S473) across the cell line panel and observed significantly higher pAkt (S473) in basal-like cell lines resistant to MEK inhibition (P < 0.001, Student’s t test; Fig. 1A). This is consistent with recent findings that loss of PTEN is strongly associated with high levels of pAkt in breast cancer cell lines and tumors [30], and suggests a model in which activation of Akt signaling via PTEN loss may desensitize a www.aacrjournals.org subset of basal-like breast cancer cells to MEK inhibition
Summary
The pathways underlying basal-like breast cancer are poorly understood, and as yet, there is no approved targeted therapy for this disease. Genetic and biochemical analyses of MEK function have suggested that MEK activity is necessary for the transforming and proliferative effects of this pathway, suggesting that therapeutics that completely inhibit MEK function may have utility in the treatment of cancers driven by activation of the RAS/RAF axis Such efforts have led to the development of www.aacrjournals.org. We find that basal-like breast cancer models are sensitive in vitro and in vivo to the inhibitory effects of mitogenactivated protein kinase kinase (MEK) inhibition relative to luminal and HER2-amplified tumors and identify the tumor suppressor PTEN as a negative predictor factor for response to MEK inhibition.We find that a combination of MEK and phosphatidylinositol 3-kinase inhibitors results in enhanced efficacy in both PTEN wild-type and PTEN-null basal-like tumors and provide a mechanistic explanation for this observation. Our studies provide a rational hypothesis for biomarker evaluation and patient stratification in clinical trials seeking to evaluate the efficacy of MEK and phosphatidylinositol 3-kinase inhibitor treatment in this poor-prognosis tumor type
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