Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib

K. Yonesaka, K. Hirotani, H. Kawakami, M. Takeda, H. Kaneda, K. Sakai, I. Okamoto, K. Nishio, P. A. Jänne, K. Nakagawa

Research output: Contribution to journalArticle

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Abstract

Human epidermal growth factor receptor (HER) 3 is aberrantly overexpressed and correlates with poor prognosis in non-small cell lung cancer (NSCLC). Patritumab is a monoclonal antibody against HER3 that has shown promising results in early-phase clinical trials, but an optimal target population for the drug has yet to be identified. In the present study, we examined whether heregulin, a HER3 ligand that is also overexpressed in a subset of NSCLC, can be used as a biomarker to predict the antitumorigenic efficacy of patritumab and whether the drug can overcome the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance induced by heregulin. Patritumab sensitivity was associated with heregulin expression, which, when abolished, resulted in the loss of HER3 and AKT activation and growth arrest. Furthermore, heregulin overexpression induced EGFR TKI resistance in NSCLC cells harbouring an activating EGFR mutation, while HER3 and AKT activation was maintained in the presence of erlotinib in heregulin-overexpressing, EGFR-mutant NSCLC cells. Sustained HER3-AKT activation was blocked by combining erlotinib with either anti-HER2 or anti-HER3 antibody. Notably, heregulin was upregulated in tissue samples from an NSCLC patient who had an activating EGFR mutation but was resistant to the TKI gefitinib. These results indicate that patritumab can overcome heregulin-dependent EGFR inhibitor resistance in NSCLC in vitro and in vivo and suggest that it can be used in combination with EGFR TKIs to treat a subset of heregulin-overexpressing NSCLC patients.

Original languageEnglish
Pages (from-to)878-886
Number of pages9
JournalOncogene
Volume35
Issue number7
DOIs
Publication statusPublished - Feb 18 2016

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Neuregulin-1
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Monoclonal Antibodies
Protein-Tyrosine Kinases
Mutation
U3-1287
Erlotinib Hydrochloride
Health Services Needs and Demand
Pharmaceutical Preparations
Anti-Idiotypic Antibodies
Biomarkers
Clinical Trials
Ligands

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib. / Yonesaka, K.; Hirotani, K.; Kawakami, H.; Takeda, M.; Kaneda, H.; Sakai, K.; Okamoto, I.; Nishio, K.; Jänne, P. A.; Nakagawa, K.

In: Oncogene, Vol. 35, No. 7, 18.02.2016, p. 878-886.

Research output: Contribution to journalArticle

Yonesaka, K, Hirotani, K, Kawakami, H, Takeda, M, Kaneda, H, Sakai, K, Okamoto, I, Nishio, K, Jänne, PA & Nakagawa, K 2016, 'Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib', Oncogene, vol. 35, no. 7, pp. 878-886. https://doi.org/10.1038/onc.2015.142
Yonesaka, K. ; Hirotani, K. ; Kawakami, H. ; Takeda, M. ; Kaneda, H. ; Sakai, K. ; Okamoto, I. ; Nishio, K. ; Jänne, P. A. ; Nakagawa, K. / Anti-HER3 monoclonal antibody patritumab sensitizes refractory non-small cell lung cancer to the epidermal growth factor receptor inhibitor erlotinib. In: Oncogene. 2016 ; Vol. 35, No. 7. pp. 878-886.
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