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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Research Article

Combining Onartuzumab with Erlotinib Inhibits Growth of Non-Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression

Yuji Sano, Eri Hashimoto, Noriaki Nakatani, Masaichi Abe, Yasuko Satoh, Kiyoaki Sakata, Toshihiko Fujii, Kaori Fujimoto-Ouchi, Masamichi Sugimoto, Shigehisa Nagahashi, Masahiro Aoki, Hiroshi Motegi, Eiichi Sasaki and Yasushi Yatabe
Yuji Sano
Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd.
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  • For correspondence: sanoyuj@chugai-pharm.co.jp
Eri Hashimoto
Kamakura Research Laboratories, Chugai Pharmaceutical Co. Ltd.
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Noriaki Nakatani
Project Lifecycle Management Unit, Chugai Pharmaceutical Co., Ltd.
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Masaichi Abe
Clinical plannning research Dept., Chugai Pharmaceutical Co., Ltd
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Yasuko Satoh
Research Division, Chugai Pharmaceutical Co., Ltd
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Kiyoaki Sakata
Pharmaceutical Research Department 2, Chugai Pharmaceutical Co., LTD.
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Toshihiko Fujii
Pharmaceutical Research Department 2, Chugai Pharmaceutical Co., LTD.
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Kaori Fujimoto-Ouchi
Discovery Pharmacology Department 2, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd
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Masamichi Sugimoto
Pharmaceutical Research Dept., Chugai Pharmaceutical Co. Ltd.
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Shigehisa Nagahashi
Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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Masahiro Aoki
Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd.
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Hiroshi Motegi
Project Lifecycle Management Unit, Chugai Pharmaceutical Co., Ltd.
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Eiichi Sasaki
Dept. of Pathology, Aichi Cancer Center
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Yasushi Yatabe
Pathology and Molecular Diagnostics, Aichi Cancer Center
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DOI: 10.1158/1535-7163.MCT-14-0456
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Abstract

Erlotinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI), benefits survival of non-small cell lung cancer (NSCLC) patients who harbor activating EGFR mutations. However, elevated expression of hepatocyte growth factor (HGF), a ligand of the MET receptor tyrosine kinase, causes erlotinib resistance. Since onartuzumab, a monovalent antibody to MET, blocks HGF-induced MET activation, the addition of onartuzumab to erlotinib may improve therapy 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 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 NSCLC patients 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.

  • Received June 5, 2014.
  • Revision received November 17, 2014.
  • Accepted December 2, 2014.
  • Copyright © 2014, American Association for Cancer Research.
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Published OnlineFirst December 18, 2014
doi: 10.1158/1535-7163.MCT-14-0456

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Combining Onartuzumab with Erlotinib Inhibits Growth of Non-Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression
Yuji Sano, Eri Hashimoto, Noriaki Nakatani, Masaichi Abe, Yasuko Satoh, Kiyoaki Sakata, Toshihiko Fujii, Kaori Fujimoto-Ouchi, Masamichi Sugimoto, Shigehisa Nagahashi, Masahiro Aoki, Hiroshi Motegi, Eiichi Sasaki and Yasushi Yatabe
Mol Cancer Ther December 18 2014 DOI: 10.1158/1535-7163.MCT-14-0456

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Combining Onartuzumab with Erlotinib Inhibits Growth of Non-Small Cell Lung Cancer with Activating EGFR Mutations and HGF Overexpression
Yuji Sano, Eri Hashimoto, Noriaki Nakatani, Masaichi Abe, Yasuko Satoh, Kiyoaki Sakata, Toshihiko Fujii, Kaori Fujimoto-Ouchi, Masamichi Sugimoto, Shigehisa Nagahashi, Masahiro Aoki, Hiroshi Motegi, Eiichi Sasaki and Yasushi Yatabe
Mol Cancer Ther December 18 2014 DOI: 10.1158/1535-7163.MCT-14-0456
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Molecular Cancer Therapeutics
eISSN: 1538-8514
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