title: PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors.
abstract: OBJECTIVE
  We sought to determine whether phosphoinositide 3-kinase (PI3K) pathway mutation or activation state and rapamycin-induced feedback loop activation of Akt is associated with rapamycin sensitivity or resistance.
  
  
  METHODS
  Cancer cell lines were tested for rapamycin sensitivity, Akt phosphorylation, and mTOR target inhibition. Mice injected with breast or neuroendocrine cancer cells and patients with neuroendocrine tumor (NET) were treated with rapalogs and Akt phosphorylation was assessed.
  
  
  RESULTS
  Thirty-one cell lines were rapamycin sensitive (RS) and 12 were relatively rapamycin resistant (RR; IC(50) > 100 nmol/L). Cells with PIK3CA and/or PTEN mutations were more likely to be RS (P = 0.0123). Akt phosphorylation (S473 and T308) was significantly higher in RS cells (P < 0.0001). Rapamycin led to a significantly greater pathway inhibition and greater increase in p-Akt T308 (P < 0.0001) and p-Akt S473 (P = 0.0009) in RS cells. Rapamycin and everolimus significantly increased Akt phosphorylation but inhibited growth in an in vivo NET model (BON). In patients with NETs treated with everolimus and octreotide, progression-free survival correlated with p-Akt T308 in pretreatment (R = 0.4762, P = 0.0533) and on-treatment tumor biopsies (R = 0.6041, P = 0.0102). Patients who had a documented partial response were more likely to have an increase in p-Akt T308 with treatment compared with nonresponders (P = 0.0146).
  
  
  CONCLUSIONS
  PIK3CA/PTEN genomic aberrations and high p-Akt levels are associated with rapamycin sensitivity in vitro. Rapamycin-mediated Akt activation is greater in RS cells, with a similar observation in patients with clinical responses on exploratory biomarker analysis; thus feedback loop activation of Akt is not a marker of resistance but rather may function as an indicator of rapamycin activity.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. fmeric@mdanderson.org
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.forename: Argun
authors.initials: A
authors.lastname: Akcakanat
authors.forename: Huiqin
authors.initials: H
authors.lastname: Chen
authors.forename: Kim-Anh
authors.initials: KA
authors.lastname: Do
authors.forename: Takafumi
authors.initials: T
authors.lastname: Sangai
authors.forename: Farrell
authors.initials: F
authors.lastname: Adkins
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Asif
authors.initials: A
authors.lastname: Rashid
authors.forename: Katherine
authors.initials: K
authors.lastname: Crosby
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Alexandria T
authors.initials: AT
authors.lastname: Phan
authors.forename: Robert A
authors.initials: RA
authors.lastname: Wolff
authors.forename: Sanjay
authors.initials: S
authors.lastname: Gupta
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: James
authors.initials: J
authors.lastname: Yao
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000235:genetics*; D018278:Carcinoma, Neuroendocrine / Q000235:genetics*; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D000068338:Everolimus; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000032:analysis* / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: D000903:Antibiotics, Antineoplastic; D014408:Biomarkers, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C484760:PIK3CA protein, human; C494929:PTEN protein, human