title: GDC-0941, a novel class I selective PI3K inhibitor, enhances the efficacy of docetaxel in human breast cancer models by increasing cell death in vitro and in vivo.
abstract: OBJECTIVE
  Docetaxel is a front-line standard-of-care chemotherapeutic drug for the treatment of breast cancer. Phosphoinositide 3-kinases (PI3K) are lipid kinases that regulate breast tumor cell growth, migration, and survival. The current study was intended to determine whether GDC-0941, an orally bioavailable class I selective PI3K inhibitor, enhances the antitumor activity of docetaxel in human breast cancer models in vitro and in vivo.
  
  
  METHODS
  A panel of 25 breast tumor cell lines representing HER2+, luminal, and basal subtypes were treated with GDC-0941, docetaxel, or the combination of both drugs and assayed for cellular viability, modulation of PI3K pathway markers, and apoptosis induction. Drug combination effects on cellular viability were also assessed in nontransformed MCF10A human mammary epithelial cells. Human xenografts of breast cancer cell lines and patient-derived tumors were used to assess efficacy of GDC-0941 and docetaxel in vivo.
  
  
  RESULTS
  Combination of GDC-0941 and docetaxel decreased the cellular viability of breast tumor cell lines in vitro but to variable degrees of drug synergy. Compared with nontransformed MCF10A cells, the addition of both drugs resulted in stronger synergistic effects in a subset of tumor cell lines that were not predicted by breast cancer subtype. In xenograft models, GDC-0941 enhanced the antitumor activity of docetaxel with maximum combination efficacy observed within 1 hour of administering both drugs. GDC-0941 increased the rate of apoptosis in cells arrested in mitosis upon cotreatment with docetaxel.
  
  
  CONCLUSIONS
  GDC-0941 augments the efficacy of docetaxel by increasing drug-induced apoptosis in breast cancer models.
authors.affiliation: Department of Translational Oncology, Genentech, Inc., San Francisco, CA, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Wallin
authors.forename: Jane
authors.initials: J
authors.lastname: Guan
authors.forename: Wei Wei
authors.initials: WW
authors.lastname: Prior
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Lee
authors.forename: Leanne
authors.initials: L
authors.lastname: Berry
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Belmont
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Lori S
authors.initials: LS
authors.lastname: Friedman
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides / Q000008:administration & dosage*; D043823:Taxoids / Q000008:administration & dosage*
chemical_list: D000077143:Docetaxel; D007191:Indazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D013449:Sulfonamides; D043823:Taxoids; C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine