title: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells.
abstract: Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC(50)s (range, 0.010-18.6 micromol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (>9 months) in trastuzumab-containing (100 microg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 12-145 Factor Building, 10945 Le Conte Avenue, Los Angeles, CA 90095-1678, USA. gkonecny@ucla.edu
authors.forename: Gottfried E
authors.initials: GE
authors.lastname: Konecny
authors.forename: Mark D
authors.initials: MD
authors.lastname: Pegram
authors.forename: Natarajan
authors.initials: N
authors.lastname: Venkatesan
authors.forename: Richard
authors.initials: R
authors.lastname: Finn
authors.forename: Guorong
authors.initials: G
authors.lastname: Yang
authors.forename: Martina
authors.initials: M
authors.lastname: Rahmeh
authors.forename: Michael
authors.initials: M
authors.lastname: Untch
authors.forename: David W
authors.initials: DW
authors.lastname: Rusnak
authors.forename: Glenn
authors.initials: G
authors.lastname: Spehar
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mullin
authors.forename: Barry R
authors.initials: BR
authors.lastname: Keith
authors.forename: Tona M
authors.initials: TM
authors.lastname: Gilmer
authors.forename: Mark
authors.initials: M
authors.lastname: Berger
authors.forename: Karl C
authors.initials: KC
authors.lastname: Podratz
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Slamon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010766:Phosphorylation; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D000068878:Trastuzumab; D023041:Xenograft Model Antitumor Assays; D048490:raf Kinases / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D000077341:Lapatinib; D051058:Oncogene Protein v-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D048490:raf Kinases