title: Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.
abstract: OBJECTIVE
  We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity.
  
  
  METHODS
  MK-2206 effects on cell signaling were assessed in vitro and in vivo. Its antitumor efficacy was assessed in vitro in a panel of cancer cell lines with differing PIK3CA and PTEN status. Its in vivo efficacy was tested as a single agent and in combination with paclitaxel.
  
  
  RESULTS
  MK-2206 inhibited Akt signaling and cell-cycle progression, and increased apoptosis in a dose-dependent manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA mutations were significantly more sensitive to MK-2206; however, several lines with PTEN/PIK3CA mutations were MK-2206 resistant. siRNA knockdown of PTEN in breast cancer cells increased Akt phosphorylation concordant with increased MK-2206 sensitivity. Stable transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and had less growth inhibition with Akt siRNA knockdown. In PTEN-mutant ZR75-1 breast cancer xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor growth. In vitro, MK-2206 showed a synergistic interaction with paclitaxel in MK-2206-sensitive cell lines, and this combination had significantly greater antitumor efficacy than either agent alone in vivo.
  
  
  CONCLUSIONS
  MK-2206 has antitumor activity alone and in combination with chemotherapy. This activity may be greater in tumors with PTEN loss or PIK3CA mutation, providing a strategy for patient enrichment in clinical trials.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sangai
authors.forename: Argun
authors.initials: A
authors.lastname: Akcakanat
authors.forename: Huiqin
authors.initials: H
authors.lastname: Chen
authors.forename: Emily
authors.initials: E
authors.lastname: Tarco
authors.forename: Yun
authors.initials: Y
authors.lastname: Wu
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.forename: Todd W
authors.initials: TW
authors.lastname: Miller
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D054316:Biomarkers, Pharmacological; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D004357:Drug Synergism; D005260:Female; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D054316:Biomarkers, Pharmacological; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D017239:Paclitaxel