title: Combining onartuzumab with erlotinib inhibits growth of non-small cell lung cancer with activating EGFR mutations and HGF overexpression.
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.
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan. sanoyuj@chugai-pharm.co.jp.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sano
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Hashimoto
authors.affiliation: Project Lifecycle Management Unit, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Nakatani
authors.affiliation: Clinical Development Division, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan.
authors.forename: Masaichi
authors.initials: M
authors.lastname: Abe
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Satoh
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Kiyoaki
authors.initials: K
authors.lastname: Sakata
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Fujii
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Fujimoto-Ouchi
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Nagahashi
authors.affiliation: Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Aoki
authors.affiliation: Project Lifecycle Management Unit, Chugai Pharmaceutical Co., Ltd., Chuo-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Motegi
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Aichi, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Sasaki
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Aichi, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008819:Mice, Nude; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C584058:onartuzumab