Department of Thoracic Surgery, Weifang People's Hospital, Shandong Second Medical University, Weifang, 261041, Shandong Province, China.
Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong Province, China.
Cell Death Dis. 2024 Jun 25;15(6):447. doi: 10.1038/s41419-024-06843-y.
There is a paucity of comprehensive knowledge pertaining to the underlying mechanisms leading to gefitinib resistance in individuals diagnosed NSCLC harboring EGFR-sensitive mutations who inevitably develop resistance to gefitinib treatment within six months to one year. In our preceding investigations, we have noted a marked upregulation of IGFBP2 in the neoplastic tissues of NSCLC, predominantly in the periphery of the tissue, implying its plausible significance in NSCLC. Consequently, in the current research, we delved into the matter and ascertained the molecular mechanisms that underlie the participation of IGFBP2 in the emergence of gefitinib resistance in NSCLC cells. Firstly, the expression of IGFBP2 in the bronchoalveolar lavage fluid and lung cancer tissues of 20 NSCLC patients with gefitinib tolerance was found to be significantly higher than that of non-tolerant patients. Furthermore, in vitro and in vivo experiments demonstrated that IGFBP2 plays a significant role in the acquisition of gefitinib resistance. Mechanistically, IGFBP2 can activate STAT3 to enhance the transcriptional activity of CXCL1, thereby increasing the intracellular expression level of CXCL1, which contributes to the survival of lung cancer cells in the gefitinib environment. Additionally, we identified ITGA5 as a key player in IGFBP2-mediated gefitinib resistance, but it does not function as a membrane receptor in the process of linking IGFBP2 to intracellular signaling transduction. In conclusion, this study demonstrates the promoting role and mechanism of IGFBP2 in acquired gefitinib resistance caused by non-EGFR secondary mutations, suggesting the potential of IGFBP2 as a biomarker for gefitinib resistance and a potential intervention target.
针对 EGFR 敏感突变的 NSCLC 患者在接受吉非替尼治疗后 6 个月至 1 年内不可避免地产生耐药性这一现象，其背后的潜在机制尚未得到全面的认识。在我们之前的研究中，我们注意到 IGFBP2 在 NSCLC 的肿瘤组织中显著上调，主要集中在组织的周边，这表明其在 NSCLC 中可能具有重要意义。因此，在当前的研究中，我们深入探讨了 IGFBP2 参与 NSCLC 细胞对吉非替尼耐药的分子机制。首先，我们发现 20 例对吉非替尼耐受的 NSCLC 患者的支气管肺泡灌洗液和肺癌组织中 IGFBP2 的表达明显高于非耐受患者。此外，体外和体内实验表明 IGFBP2 在获得吉非替尼耐药中起重要作用。从机制上讲，IGFBP2 可以激活 STAT3 增强 CXCL1 的转录活性，从而增加 CXCL1 的细胞内表达水平，促进肺癌细胞在吉非替尼环境下的存活。此外，我们确定 ITGA5 是 IGFBP2 介导的吉非替尼耐药中的关键因子，但它在 IGFBP2 与细胞内信号转导的连接过程中不作为膜受体发挥作用。综上所述，本研究表明 IGFBP2 在非 EGFR 二次突变引起的获得性吉非替尼耐药中具有促进作用及其机制，提示 IGFBP2 作为吉非替尼耐药的潜在标志物和干预靶点的可能性。
