title: In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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: Translational Oncology, Genentech, Inc., South San Francisco, California 94080, USA.
authors: Klaus P
authors: KP
authors: Hoeflich
authors: Carol
authors: C
authors: O'Brien
authors: Zachary
authors: Z
authors: Boyd
authors: Guy
authors: G
authors: Cavet
authors: Steve
authors: S
authors: Guerrero
authors: Kenneth
authors: K
authors: Jung
authors: Tom
authors: T
authors: Januario
authors: Heidi
authors: H
authors: Savage
authors: Elizabeth
authors: E
authors: Punnoose
authors: Tom
authors: T
authors: Truong
authors: Wei
authors: W
authors: Zhou
authors: Leanne
authors: L
authors: Berry
authors: Lesley
authors: L
authors: Murray
authors: Lukas
authors: L
authors: Amler
authors: Marcia
authors: M
authors: Belvin
authors: Lori S
authors: LS
authors: Friedman
authors: Mark R
authors: MR
authors: Lackner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D015151:Immunoblotting; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D048369:MAP Kinase Kinase 1; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors