title: Overcoming chemoresistance of small-cell lung cancer through stepwise HER2-targeted antibody-dependent cell-mediated cytotoxicity and VEGF-targeted antiangiogenesis.
abstract: Small-cell lung cancer (SCLC) easily recurs with a multidrug resistant phenotype. However, standard therapeutic strategies for relapsed SCLC remain unestablished. We found that human epidermal growth factor receptor 2 (HER2) is not only expressed in pretreated human SCLC specimens, but is also upregulated when HER2-positive SCLC cells acquire chemoresistance. Trastuzumab induced differential levels of antibody-dependent cell-mediated cytotoxicity (ADCC) to HER2-positive SCLC cells. Furthermore, as a mechanism of the differential levels of ADCC, we have revealed that coexpression of intracellular adhesion molecule (ICAM)-1 on SCLC cells is essential to facilitate and accelerate the trastuzumab-mediated ADCC. Although SN-38-resistant SCLC cells lacking ICAM-1 expression were still refractory to trastuzumab, their in vivo growth was significantly suppressed by bevacizumab treatment due to dependence on their distinctive and abundant production of vascular endothelial growth factor. Collectively, stepwise treatment with trastuzumab and bevacizumab is promising for the treatment of chemoresistant SCLC.
authors.affiliation: Department of Respiratory Medicine, Allergy and Rheumatic Diseases, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Minami
authors.forename: Takashi
authors.initials: T
authors.lastname: Kijima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kohmo
authors.forename: Hisashi
authors.initials: H
authors.lastname: Arase
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Otani
authors.forename: Izumi
authors.initials: I
authors.lastname: Nagatomo
authors.forename: Ryo
authors.initials: R
authors.lastname: Takahashi
authors.forename: Kotaro
authors.initials: K
authors.lastname: Miyake
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Higashiguchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Morimura
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ihara
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsujino
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Hirata
authors.forename: Koji
authors.initials: K
authors.lastname: Inoue
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Takeda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kida
authors.forename: Isao
authors.initials: I
authors.lastname: Tachibana
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018799:Intercellular Adhesion Molecule-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A
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