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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
3
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pubmed:dateCreated |
2006-2-2
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal, Humanized,
http://linkedlifedata.com/resource/pubmed/chemical/Extracellular Signal-Regulated MAP...,
http://linkedlifedata.com/resource/pubmed/chemical/Oncogene Protein v-akt,
http://linkedlifedata.com/resource/pubmed/chemical/Quinazolines,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Epidermal Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, erbB-2,
http://linkedlifedata.com/resource/pubmed/chemical/lapatinib,
http://linkedlifedata.com/resource/pubmed/chemical/raf Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/trastuzumab
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pubmed:status |
MEDLINE
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pubmed:month |
Feb
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pubmed:issn |
0008-5472
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pubmed:author |
pubmed-author:BergerMarkM,
pubmed-author:FinnRichardR,
pubmed-author:GilmerTona MTM,
pubmed-author:KeithBarry RBR,
pubmed-author:KonecnyGottfried EGE,
pubmed-author:MullinRobert JRJ,
pubmed-author:PegramMark DMD,
pubmed-author:PodratzKarl CKC,
pubmed-author:RahmehMartinaM,
pubmed-author:RusnakDavid WDW,
pubmed-author:SlamonDennis JDJ,
pubmed-author:SpeharGlennG,
pubmed-author:UntchMichaelM,
pubmed-author:VenkatesanNatarajanN,
pubmed-author:YangGuorongG
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pubmed:issnType |
Print
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pubmed:day |
1
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pubmed:volume |
66
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
1630-9
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:16452222-Animals,
pubmed-meshheading:16452222-Antibodies, Monoclonal,
pubmed-meshheading:16452222-Antibodies, Monoclonal, Humanized,
pubmed-meshheading:16452222-Antineoplastic Combined Chemotherapy Protocols,
pubmed-meshheading:16452222-Breast Neoplasms,
pubmed-meshheading:16452222-Cell Cycle,
pubmed-meshheading:16452222-Cell Line, Tumor,
pubmed-meshheading:16452222-Drug Interactions,
pubmed-meshheading:16452222-Drug Screening Assays, Antitumor,
pubmed-meshheading:16452222-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:16452222-Female,
pubmed-meshheading:16452222-Humans,
pubmed-meshheading:16452222-Mice,
pubmed-meshheading:16452222-Mice, SCID,
pubmed-meshheading:16452222-Oncogene Protein v-akt,
pubmed-meshheading:16452222-Phosphorylation,
pubmed-meshheading:16452222-Quinazolines,
pubmed-meshheading:16452222-Receptor, Epidermal Growth Factor,
pubmed-meshheading:16452222-Receptor, erbB-2,
pubmed-meshheading:16452222-Xenograft Model Antitumor Assays,
pubmed-meshheading:16452222-raf Kinases
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pubmed:year |
2006
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pubmed:articleTitle |
Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells.
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pubmed: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
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pubmed:publicationType |
Journal Article
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