RRC ID 67406
著者 Sano Y, Hashimoto E, Nakatani N, Abe M, Satoh Y, Sakata K, Fujii T, Fujimoto-Ouchi K, Sugimoto M, Nagahashi S, Aoki M, Motegi H, Sasaki E, Yatabe Y.
タイトル Combining onartuzumab with erlotinib inhibits growth of non-small cell lung cancer with activating EGFR mutations and HGF overexpression.
ジャーナル Mol Cancer Ther
Abstract Erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), benefits survival of patients with non-small cell lung cancer (NSCLC) who harbor activating EGFR mutations. However, elevated expression of hepatocyte growth factor (HGF), a ligand of the MET receptor tyrosine kinase, causes erlotinib resistance. Because onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapeutic efficacy. We engineered the human NSCLC cell line PC-9 (MET-positive cells harboring an exon 19 deletion of EGFR) to overexpress hHGF and evaluated the effects of an onartuzumab and erlotinib combination in vitro and in vivo in xenograft models. A stable clone of PC-9/hHGF was less sensitive to erlotinib than the parental PC-9, and the addition of onartuzumab to erlotinib suppressed the proliferation of these cells in vitro. In PC-9/hHGF xenograft tumors, onartuzumab or erlotinib alone minimally inhibited tumor growth; however, combining onartuzumab and erlotinib markedly suppressed tumor growth. The total MET protein level was decreased in PC-9/hHGF cells, because MET is constitutively phosphorylated by autocrine HGF, leading to its ubiquitination and degradation. Onartuzumab reduced phospho-MET levels, inhibited MET ubiquitination, and consequently restored MET protein levels. Moreover, in NSCLC clinical specimens harboring activating EGFR mutations, more than 30% of patients expressed high levels of HGF. Our findings raised the possibility that patients with NSCLC with EGFR mutations who express high levels of HGF may benefit from onartuzumab and erlotinib combination therapy, and that HGF can be a novel biomarker for selecting such patients.
巻・号 14(2)
ページ 533-41
公開日 2015-2-1
DOI 10.1158/1535-7163.MCT-14-0456
PII 1535-7163.MCT-14-0456
PMID 25522765
MeSH Animals Antibodies, Monoclonal / pharmacology Antibodies, Monoclonal / therapeutic use* Antineoplastic Agents / pharmacology Antineoplastic Agents / therapeutic use Antineoplastic Combined Chemotherapy Protocols / pharmacology Antineoplastic Combined Chemotherapy Protocols / therapeutic use Carcinoma, Non-Small-Cell Lung / drug therapy* Carcinoma, Non-Small-Cell Lung / enzymology Carcinoma, Non-Small-Cell Lung / pathology* Cell Line, Tumor Cell Proliferation / drug effects ErbB Receptors / genetics* Erlotinib Hydrochloride Extracellular Signal-Regulated MAP Kinases / metabolism Female Gene Expression Regulation, Neoplastic / drug effects Hepatocyte Growth Factor / genetics Hepatocyte Growth Factor / metabolism* Humans Lung Neoplasms / drug therapy Lung Neoplasms / enzymology Lung Neoplasms / pathology Mice, Nude Mutation / genetics* Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use Proto-Oncogene Proteins c-akt / metabolism Proto-Oncogene Proteins c-met Quinazolines / pharmacology Quinazolines / therapeutic use* RNA, Messenger / genetics RNA, Messenger / metabolism Xenograft Model Antitumor Assays
IF 5.615
リソース情報
ヒト・動物細胞 KP4(RCB1005)