title: Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT.
abstract: OBJECTIVE
  Altered PI3K/mTOR signaling is implicated in the pathogenesis of a number of breast cancers, including those resistant to hormonal and HER2-targeted therapies.
  
  
  METHODS
  The activity of four classes of PI3K/mTOR inhibitory molecules, including a pan-PI3K inhibitor (NVP-BKM120), a p110α isoform-specific PI3K inhibitor (NVP-BYL719), an mTORC1-specific inhibitor (NVP-RAD001), and a dual PI3K/mTORC1/2 inhibitor (NVP-BEZ235), was evaluated both in vitro and in vivo against a panel of 48 human breast cell lines.
  
  
  RESULTS
  Each agent showed significant antiproliferative activity in vitro, particularly in luminal estrogen receptor-positive and/or HER2(+) cell lines harboring PI3K mutations. In addition, monotherapy with each of the four inhibitors led to significant inhibition of in vivo growth in HER2(+) breast cancer models. The PI3K/mTOR pathway inhibitors were also effective in overcoming both de novo and acquired trastuzumab resistance in vitro and in vivo. Furthermore, combined targeting of HER2 and PI3K/mTOR leads to increased apoptosis in vitro and induction of tumor regression in trastuzumab-resistant xenograft models. Finally, as previously shown, targeting mTORC1 alone with RAD001 leads to consistent feedback activation of AKT both in vitro and in vivo, whereas the dual mTOR1-2/PI3K inhibitor BEZ235 eliminates this feedback loop. However, despite these important signaling differences, both molecules are equally effective in inhibiting tumor cell proliferation both in vitro and in vivo.
  
  
  CONCLUSIONS
  These preclinical data support the findings of the BOLERO 3 trial that shows that targeting of the PI3K/mTOR pathway in combination with trastuzumab is beneficial in trastuzumab-resistant breast cancer.
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California; nobrien@mednet.ucla.edu.
authors.forename: Neil A
authors.initials: NA
authors.lastname: O'Brien
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Karen
authors.initials: K
authors.lastname: McDonald
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Luo
authors.initials: L
authors.lastname: Tong
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Erika
authors.initials: E
authors.lastname: von Euw
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Ondrej
authors.initials: O
authors.lastname: Kalous
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Dylan
authors.initials: D
authors.lastname: Conklin
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Sara A
authors.initials: SA
authors.lastname: Hurvitz
authors.affiliation: Novartis Pharmaceuticals, Cambridge, Massachusetts; and.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: di Tomaso
authors.affiliation: Novartis Pharmaceuticals, Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Schnell
authors.affiliation: Novartis Pharmaceuticals, Cambridge, Massachusetts; and.
authors.forename: Ronald
authors.initials: R
authors.lastname: Linnartz
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
authors.affiliation: Novartis Pharmaceuticals, Cambridge, Massachusetts; and.
authors.forename: Samit
authors.initials: S
authors.lastname: Hirawat
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine, Geffen School of Medicine at UCLA, Los Angeles, California;
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab