The Role of IGFBP7 in EGFR-TKI Acquired Resistant Lung Cancer

Hu, Qiongge; Ruan, Wenjing; Zhu, Huiqi; Yan, Chao; Xu, Yiming

doi:10.30476/mejc.2026.107427.2290

The Role of IGFBP7 in EGFR-TKI Acquired Resistant Lung Cancer

Document Type : Original Article(s)

Authors

Qiongge Hu ¹

Wenjing Ruan ²

Huiqi Zhu ²

Chao Yan ²

Yiming Xu ²

¹ Department of Radiation Oncology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

² Department of Respiratory Medicine, Regional Medical Center for the National Institute of Respiratory Disease, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China

https://doi.org/10.30476/mejc.2026.107427.2290

Abstract

Background: Targeted drug resistance is a bottleneck in lung cancer treatment. The present study aimed to explore the role of insulin-like growth factor-binding protein 7 (IGFBP7) in epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) acquired resistance.
Method: A retrospective case-control study was conducted in-vitro on cell lines. Cell lines experiments in-vitro and stable resistant strains of PC9 cells were selected under 5μM gefitinib. IGFBP7 and the related insulin-like growth factor-1 receptor (IGF-1R)/insulin receptor (IR) signaling pathway proteins were detected by western blot. SiRNA interference was used to downregulate IGFBP7 level in the PC9-Gefitinib resistant (PC9-GR) cells. Cell proliferation assay and invasion assay were carried out. The serum level of IGFBP7 and insulin was detected in EGFR-TKI acquired resistant and EGFR-TKI sensitive patients. Quantitative data was expressed as mean ± standard deviation values. Chi-square test was used to compare the baseline clinical characteristics of the patients. One-way analysis of variance was used to detect the differences between groups. A P-value<0.05 was considered statistically significant.
Results: The upregulation of IGFBP7, Tyr1135/1136, IR-β, IRS1 and IGF-1R protein was observed. The interference of IGFBP7 slowed down the proliferation rate and weakened the invasion ability of PC9-GR cells. The EGFR-TKI resistant subgroup analysis according to the T790 mutation (T790M) status suggested that IGFBP7’s concentration in the T790M negative group was significantly higher than that in the T790M positive group (53.21 ± 49.15 versus 14.37 ± 0.78, P < 0.05).
Conclusion: IGFBP7 and insulin-IGF-1R-IR network contributed to EGFR-TKI acquired resistance. IGFBP7 functioned both in T790M positive and T790M negative EGFR-TKI acquired resistance.

Keywords

Insulin-like growth factor binding protein-related protein 1

Targeted drug resistance

Lung neoplasms

Subjects

Cancer Biology/Genetics

Please cite this article as:

Hu Q, Ruan W, Zhu H, Yan C, Xu Y. The role of IGFBP7 in EGFR-TKI acquired resistant lung cancer. Middle East J Cancer. 2026;17(4):312-20. doi: 10.30476/mejc.2026.107427.2290.

Zhang YL, Yuan JQ, Wang KF, Fu XH, Han XR, Threapleton D, et al. The prevalence of EGFR mutation in patients with non-small cell lung cancer: a systematic review and meta-analysis. Oncotarget. 2016;7(48):78985-93. doi: 10.18632/oncotarget.12587. PMID: 27738317; PMCID: PMC5346692.
Westover D, Zugazagoitia J, Cho BC, Lovly CM, Paz-Ares L. Mechanisms of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Ann Oncol. 2018;29(suppl_1):i10-i19. doi: 10.1093/annonc/mdx703. PMID: 29462254; PMCID: PMC6454547.
Fang W, Wu L, Meng X, Yao Y, Zuo W, Yao W, et al. Sacituzumab tirumotecan in EGFR-TKI-resistant, EGFR-mutated advanced NSCLC. N Engl J Med. 2026;394(1):13-26. doi: 10.1056/NEJMoa2512071. PMID: 41124220.
He J, Huang Z, Han L, Gong Y, Xie C. Mechanisms and management of 3rd‑generation EGFR‑TKI resistance in advanced non‑small cell lung cancer (Review). Int J Oncol. 2021;59(5):90. doi: 10.3892/ijo.2021.5270. PMID: 34558640; PMCID: PMC8562388.
Silva AP, Coelho PV, Anazetti M, Simioni PU. Targeted therapies for the treatment of non-small-cell lung cancer: Monoclonal antibodies and biological inhibitors. Hum Vaccin Immunother. 2017;13(4):843-53. doi: 10.1080/21645515.2016.1249551. PMID: 27831000; PMCID: PMC5404364.
Baxter RC. Signaling pathways of the insulin-like growth factor binding proteins. Endocr Rev. 2023;44(5):753-78. doi: 10.1210/endrev/bnad008. PMID: 36974712; PMCID: PMC10502586.
Hu Q, Zhou Y, Ying K, Ruan W. IGFBP, a novel target of lung cancer? Clin Chim Acta. 2017;466:172-7. doi: 10.1016/j.cca.2017.01.017. PMID: 28104361.
Hayakawa D, Takahashi F, Mitsuishi Y, Tajima K, Hidayat M, Winardi W, et al. Activation of insulin-like growth factor-1 receptor confers acquired resistance to osimertinib in non-small cell lung cancer with EGFR T790M mutation. Thorac Cancer. 2020;11(1):140-9. doi: 10.1111/1759-7714.13255. PMID: 31758670; PMCID: PMC6938756.
Park JH, Choi YJ, Kim SY, Lee JE, Sung KJ, Park S, et al. Activation of the IGF1R pathway potentially mediates acquired resistance to mutant-selective 3rd-generation EGF receptor tyrosine kinase inhibitors in advanced non-small cell lung cancer. Oncotarget. 2016;7(16):22005-15. doi: 10.18632/oncotarget.8013. PMID: 26980747; PMCID: PMC5008340.
Wu SG, Chang TH, Tsai MF, Liu YN, Hsu CL, Chang YL, et al. IGFBP7 drives resistance to epidermal growth factor receptor tyrosine kinase inhibition in lung cancer. Cancers (Basel). 2019;11(1):36. doi: 10.3390/cancers11010036. PMID: 30609749; PMCID: PMC6356910.
Tang X, Mu J, Ma L, Tan Q, Wang J, Tan J, et al. IGFBP7 overexpression promotes acquired resistance to AZD9291 in non-small cell lung cancer. Biochem Biophys Res Commun. 2021;571:38-45. doi: 10.1016/j.bbrc.2021.07.055. PMID: 34303194.
Fujiwara R, Taniguchi Y, Rai S, Iwata Y, Fujii A, Fujimoto K, et al. Chlorpromazine cooperatively induces apoptosis with tyrosine kinase inhibitors in EGFR-mutated lung cancer cell lines and restores the sensitivity to gefitinib in T790M-harboring resistant cells. Biochem Biophys Res Commun. 2022;626:156-66. doi: 10.1016/j.bbrc.2022.08.010. PMID: 35994825.
Gomatou G, Syrigos N, Kotteas E. Osimertinib resistance: Molecular mechanisms and emerging treatment options. Cancers (Basel). 2023;15(3):841. doi: 10.3390/cancers15030841. PMID: 36765799; PMCID: PMC9913144.
Ruan W, Kang Z, Li Y, Sun T, Wang L, Liang L, et al. Interaction between IGFBP7 and insulin: a theoretical and experimental study. Sci Rep. 2016;6:19586. doi: 10.1038/srep19586. PMID: 27101796; PMCID: PMC4840315.
Chiu HY, Chiang CM, Yeh SP, Jong DS, Wu LS, Liu HC, et al. Effects of hyperinsulinemia on acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor via the PI3K/AKT pathway in non-small cell lung cancer cells in vitro. Oncol Lett. 2020;20(5):206. doi: 10.3892/ol.2020.12069. PMID: 32963612; PMCID: PMC7491043.
Love KM, Barrett EJ, Horton WB. Metformin's impact on the microvascular response to insulin. Endocrinology. 2022;163(11):bqac162. doi: 10.1210/endocr/bqac162. PMID: 36201598; PMCID: PMC10233257.
Pan YH, Jiao L, Lin CY, Lu CH, Li L, Chen HY, et al. Combined treatment with metformin and gefitinib overcomes primary resistance to EGFR-TKIs with EGFR mutation via targeting IGF-1R signaling pathway. Biologics. 2018;12:75-86. doi: 10.2147/BTT.S166867. PMID: 30154647; PMCID: PMC6108345.
Han R, Jia Y, Li X, Zhao C, Zhao S, Liu S, et al. Concurrent use of metformin enhances the efficacy of EGFR-TKIs in patients with advanced EGFR-mutant non-small cell lung cancer-an option for overcoming EGFR-TKI resistance. Transl Lung Cancer Res. 2021;10(3):1277-91. doi: 10.21037/tlcr-20-1153. PMID: 33889509; PMCID: PMC8044488.