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Open AccessArticle

IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer

1
Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
2
Department of Internal Medicine, National Taiwan University Cancer Center, National Taiwan University, Taipei 10672, Taiwan
3
Department of Molecular Biotechnology, Da-Yeh University, Changhua 51591, Taiwan
4
Department of Medical Research, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
5
Department of Pathology, National Taiwan University Hospital, National Taiwan University, Taipei 10002, Taiwan
6
Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(1), 36; https://doi.org/10.3390/cancers11010036
Received: 10 November 2018 / Revised: 17 December 2018 / Accepted: 24 December 2018 / Published: 2 January 2019
Patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer show a dramatic response to EGFR-tyrosine kinase inhibitors (TKIs). However, acquired drug resistance eventually develops. This study explored the novel mechanisms related to TKI resistance. To identify the genes associated with TKI resistance, an integrative approach was used to analyze public datasets. Molecular manipulations were performed to investigate the roles of insulin-like growth factor binding protein 7 (IGFBP7) in lung adenocarcinoma. Clinical specimens were collected to validate the impact of IGFBP7 on the efficacy of EGFR TKI treatment. IGFBP7 mRNA expression in cancer cells isolated from malignant pleural effusions after acquired resistance to EGFR-TKI was significantly higher than in cancer cells from treatment-naïve effusions. IGFBP7 expression was markedly increased in cells with long-term TKI-induced resistance compared to in TKI-sensitive parental cells. Reduced IGFBP7 in TKI-resistant cells reversed the resistance to EGFR-TKIs and increased EGFR-TKI-induced apoptosis by up-regulating B-cell lymphoma 2 interacting mediator of cell death (BIM) and activating caspases. Suppression of IGFBP7 attenuated the phosphorylation of insulin-like growth factor 1 receptor (IGF-IR) and downstream protein kinase B (AKT) in TKI-resistant cells. Clinically, higher serum IGFBP7 levels and tumors with positive IGFBP7-immunohistochemical staining were associated with poor TKI-treatment outcomes. IGFBP7 confers resistance to EGFR-TKIs and is a potential therapeutic target for treating EGFR-TKI-resistant cancers. View Full-Text
Keywords: EGFR mutation; insulin-like growth factor binding protein 7; epidermal growth factor receptor-tyrosine kinase inhibitor; acquired resistance; lung cancer EGFR mutation; insulin-like growth factor binding protein 7; epidermal growth factor receptor-tyrosine kinase inhibitor; acquired resistance; lung cancer
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Wu, S.-G.; Chang, T.-H.; Tsai, M.-F.; Liu, Y.-N.; Hsu, C.-L.; Chang, Y.-L.; Yu, C.-J.; Shih, J.-Y. IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer. Cancers 2019, 11, 36.

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