title: Lapatinib, a dual EGFR and HER2 kinase inhibitor, selectively inhibits HER2-amplified human gastric cancer cells and is synergistic with trastuzumab in vitro and in vivo.
abstract: OBJECTIVE
  HER2 amplification occurs in 18% to 27% of gastric and gastroesophageal junction cancers. Lapatinib, a potent ATP-competitive inhibitor simultaneously inhibits both EGFR and HER2. To explore the role of HER family biology in upper gastrointestinal cancers, we evaluated the effect of lapatinib, erlotinib, and trastuzumab in a panel of molecularly characterized human upper gastrointestinal cancer cell lines and xenografts.
  
  
  METHODS
  EGFR and HER2 protein expression were determined in a panel of 14 human upper gastrointestinal cancer cell lines and HER2 status was assessed by fluorescent in situ hybridization. Dose-response curves were generated to determine sensitivity to lapatinib, erlotinib, and trastuzumab. In HER2-amplified cells, the combination of trastuzumab and lapatinib was evaluated using the median effects principal. The efficacy of lapatinib, trastuzumab, or the combination was examined in HER2-amplified xenograft models.
  
  
  RESULTS
  Lapatinib had concentration-dependent antiproliferative activity across the panel with the greatest effects in HER2-amplified cells. There was no association between EGFR protein expression and sensitivity to any of the HER-targeted agents. Cell cycle analysis revealed that lapatinib induced G(1) arrest in sensitive lines and phosphorylated AKT and phosphorylated ERK were decreased in response to lapatinib as well. The combination of lapatinib and trastuzumab was highly synergistic in inhibiting cell growth with a combination index of <1. The combination also induced greater decreases in AKT and ERK activation, G(0)-G(1) cell cycle arrest, and increased rates of apoptosis. In vivo studies showed that the combination of lapatinib and trastuzumab had greater antitumor efficacy than either drug alone.
  
  
  CONCLUSIONS
  Together, these data suggest that lapatinib has activity in HER2-amplified upper gastrointestinal cancer and supports the ongoing clinical investigation of lapatinib in patients with HER2-amplified disease.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Geffen School of Medicine at UCLA, Los Angeles, California 90404, USA. zwainberg@mednet.ucla.edu
authors.forename: Zev A
authors.initials: ZA
authors.lastname: Wainberg
authors.forename: Adrian
authors.initials: A
authors.lastname: Anghel
authors.forename: Amrita J
authors.initials: AJ
authors.lastname: Desai
authors.forename: Raul
authors.initials: R
authors.lastname: Ayala
authors.forename: Tong
authors.initials: T
authors.lastname: Luo
authors.forename: Brent
authors.initials: B
authors.lastname: Safran
authors.forename: Marlena S
authors.initials: MS
authors.lastname: Fejzo
authors.forename: J Randolph
authors.initials: JR
authors.lastname: Hecht
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
authors.forename: Richard S
authors.initials: RS
authors.lastname: Finn
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000096:biosynthesis* / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D000077341:Lapatinib; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab