IGFBP7 overexpression promotes acquired resistance to AZD9291 in non-small cell lung cancer

Xiaonan Tang; Jing Mu; Li Ma; Qifan Tan; Jinghui Wang; Jinjing Tan; Shucai Zhang

doi:10.1016/j.bbrc.2021.07.055

IGFBP7 overexpression promotes acquired resistance to AZD9291 in non-small cell lung cancer

Biochem Biophys Res Commun. 2021 Sep 24:571:38-45. doi: 10.1016/j.bbrc.2021.07.055. Epub 2021 Jul 21.

Authors

Xiaonan Tang¹, Jing Mu², Li Ma¹, Qifan Tan¹, Jinghui Wang³, Jinjing Tan⁴, Shucai Zhang⁵

Affiliations

¹ Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China.
² Department of Pathology, Beijing Chest Hospital, Capital Medical University & Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, 101149, China.
³ Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China; Department of Cellular and Molecular Biology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China.
⁴ Department of Cellular and Molecular Biology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China. Electronic address: jinjingtan@ccmu.edu.cn.
⁵ Department of Medical Oncology, Beijing Tuberculosis and Thoracic Tumor Research Institute/Beijing Chest Hospital, Capital Medical University, Beijing, 101149, China. Electronic address: sczhang6304@126.com.

PMID: 34303194
DOI: 10.1016/j.bbrc.2021.07.055

Abstract

AZD9291 (osimertinib) is the third-generation EGFR-TKI treat for EGFR mutated NSCLC patients. Despite its encouraging efficacy in clinical, acquired resistance is still inevitable. The mechanism of drug resistance needs to be further explored. In a previous study, we established an AZD9291-resistant cell strain named HCC827/AZDR. We found that insulin-like growth factor binding protein 7 (IGFBP7) expression was markedly increased in HCC827/AZDR cells and AZD9291-resistant patients by RNA sequencing and immunohistochemical analysis, respectively. Reduced IGFBP7 in HCC827/AZDR cells by si-RNA interference recovered the sensitivity to AZD9291 partially and increased AZD9291-induced cell apoptosis. Enhancing IGFBP7 expression in EGFR-mutated non-small cell lung cancer (NSCLC) cells using lentiviruses infection reduced their sensitivity to AZD9291. This study is the first to discover that high IGFBP7 expression could occur following treatment with AZD9291. This might be one of the mechanisms underlying AZD9291 resistance and a potential therapeutic target following AZD9291 resistance.

Keywords: Acquired-resistance; IGFBP7; NSCLC; Osimertinib; The third-generation EGFR-TKI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acrylamides / pharmacology
Aniline Compounds / pharmacology
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Carcinoma, Non-Small-Cell Lung / drug therapy
Carcinoma, Non-Small-Cell Lung / metabolism*
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Resistance, Neoplasm / drug effects
Drug Screening Assays, Antitumor
Humans
Insulin-Like Growth Factor Binding Proteins / genetics*
Insulin-Like Growth Factor Binding Proteins / metabolism
Lung Neoplasms / drug therapy
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology

Substances

Acrylamides
Aniline Compounds
Antineoplastic Agents
Insulin-Like Growth Factor Binding Proteins
insulin-like growth factor binding protein-related protein 1
osimertinib