title: Combined effects of lapatinib and bortezomib in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and activity of bortezomib against lapatinib-resistant breast cancer cells.
abstract: Lapatinib and bortezomib are highly active against breast cancer cells. Breast cancer patients who initially respond to lapatinib may eventually manifest acquired resistance to this treatment. Thus, the identification of novel agents that may prevent or delay the development of acquired resistance to lapatinib is critical. In the current study, we show that the combination of lapatinib and bortezomib results in a synergistic growth inhibition in human epidermal receptor 2 (HER2)-overexpressing breast cancer cells and that the combination enhances apoptosis of SK-BR-3 cells. Importantly, we found that the combination of lapatinib plus bortezomib more effectively blocked activation of the HER2 pathway in SK-BR-3 cells, compared with monotherapy. In addition, we established a model of acquired resistance to lapatinib by chronically challenging SK-BR-3 breast cancer cells with increasing concentrations of lapatinib. Here, we showed that bortezomib notably induced apoptosis of lapatinib-resistant SK-BR-3 pools and further inhibited HER2 signaling in the resistant cells. Taken together, the current data indicate a synergistic interaction between lapatinib and bortezomib in HER2-overexpressing breast cancer cells and provide the rationale for the clinical evaluation of these two noncross-resistant targeted therapies. The combination of lapatinib and bortezomib may be a potentially novel approach to prevent or delay the onset of acquired resistance to lapatinib in HER2-overxpressing/estrogen receptor (ER)-negative breast cancers.
authors.affiliation: Breast Disease Centre, Shandong Cancer Hospital and Institute, Jinan, China. mcd7301@hotmail.com
authors.forename: Chuandong
authors.initials: C
authors.lastname: Ma
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Niu
authors.forename: Jianmin
authors.initials: J
authors.lastname: Luo
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Shao
authors.forename: Kunwei
authors.initials: K
authors.lastname: Shen
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage* / Q000494:pharmacology; D000069286:Bortezomib; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D000077341:Lapatinib; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage* / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048049:Extracellular Signal-Regulated MAP Kinases; D047908:Intracellular Signaling Peptides and Proteins; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011719:Pyrazines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C436291:CDKN1B protein, human; C508053:ERBB2 protein, human