Effect of Cetuximab and <i>EGFR</i> Small Interfering RNA Combination Treatment in NSCLC Cell Lines with Wild Type <i>EGFR</i> and Use of <i>KRAS</i> as a Possible Biomarker for Treatment Responsiveness

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  • Miyake Naomi
    *Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
  • Chikumi Hiroki
    †Division of Infectious Diseases, Tottori University Hospital, Yonago 683-8504, Japan
  • Yamaguchi Kosuke
    *Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
  • Takata Miyako
    ‡Department of Pathobiological Science and Technology, School of Health Science, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
  • Takata Miki
    *Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan
  • Okada Kensaku
    †Division of Infectious Diseases, Tottori University Hospital, Yonago 683-8504, Japan
  • Kitaura Tsuyoshi
    †Division of Infectious Diseases, Tottori University Hospital, Yonago 683-8504, Japan
  • Nakamoto Masaki
    †Division of Infectious Diseases, Tottori University Hospital, Yonago 683-8504, Japan
  • Yamasaki Akira
    *Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8503, Japan

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<p>Background The epidermal growth factor receptor (EGFR) is a therapeutic target for patients with non-small cell lung cancer (NSCLC). Cetuximab is an anti-EGFR monoclonal antibody that inhibits EGFR signaling and proliferation of colorectal cancer and head and neck cancers. Since only few NSCLC patients benefit from cetuximab therapy, we evaluated a novel combination treatment using cetuximab and EGFR small interfering RNA (siRNA) to strongly suppress EGFR signaling and searched for a biomarker in NSCLC cell lines harboring wild-type EGFR.</p><p>Methods Alterations in EGFR and its downstream genes in five NSCLC cell lines (A549, Lu99, 86-2, Sq19 and Ma10) were assessed through sequencing. The protein expression levels of these molecules were assessed through western blotting. The effect of combination treatment was determined through cell proliferation assay, caspase-3/7 assay, invasion assay, and migration assay.</p><p>Results All cell lines were harboring wild-type EGFR, whereas KRAS, PTEN, TP53 and TP53 were mutated in A549 and Lu99; Lu99 and Sq19; Lu99, 86-2, Sq19 and Ma10; and A549, 86-2, and Sq19 cell lines, respectively. PTEN was not expressed in Sq19, and LKB1 was not expressed in both A549 and Sq19. TP53 was not expressed in both A549 and Lu99. The combination of cetuximab and EGFR siRNA significantly suppressed cell proliferation in 86-2, Sq19 and Ma10, which express wild-type KRAS. It induced apoptosis in A549, 86-2 and Ma10 cells, which express wild type PTEN. The combination treatment had no effect either on cell invasion nor migration in all cell lines.</p><p>Conclusion EGFR targeted therapy using the combination of cetuximab and EGFR siRNA is effective in NSCLC cell lines harboring wild-type EGFR. Wild-type KRAS may act as a potential biomarker for response to combination treatment by the induction of apoptosis in cells with wild-type PTEN.</p>

Journal

  • Yonago Acta Medica

    Yonago Acta Medica 62 (1), 085-093, 2019

    Tottori University Medical Press

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