Zheng Sijia, Cao Limin, Zhang Jiayi, Zhang Qicheng, Ren Yinghui, Wang Min, Qian Yongmei, Li Bingbing, Wu Xiang, Meng Zhaowei, Xu Ke
Tianjin Key Laboratory of Lung Cancer Metastasis and Tumor Microenvironment, Tianjin Lung Cancer Institute, Tianjin Medical University General Hospital, Tianjin 300052, China.
Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China.
J Cancer. 2025 Aug 11;16(12):3729-3745. doi: 10.7150/jca.111383. eCollection 2025.
Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI); it has achieved favorable progression-free survival (PFS) in non-small cell lung cancer (NSCLC) patients with EGFR mutation, however, the resistance occurs in most patients, and the underlying mechanism remain to be elucidated. Cancer-associated fibroblasts (CAFs) are major stromal cells in tumor microenvironment. Despite accumulating evidence suggests that CAFs contribute to drug resistance, the role of CAFs in osimertinib resistance in NSCLC is not fully understood. Here, we reported that CAFs promoted the resistance of NSCLC cells to osimertinib through enhancing stemness of NSCLC cells and reducing apoptosis induced by osimertinib. CAFs possessed a high level of Neuregulin-1 (NRG1), and CAFs-secreted NRG1 mediated the promoting effect of CAFs on osimertinib resistance, demonstrated by applying recombinant human NRG1 (rhNRG1) and NRG1 knockdown. We also found that osimertinib stimulated NRG1 secretion by CAFs, which may further enhance osimertinib resistance. Further study revealed that CAFs promoted the resistance of NSCLC cells to osimertinib via NRG1-mediated HER3/AKT/NF-κB pathway. Moreover, the mouse xenograft study demonstrated that CAFs enhanced osimertinib-treated tumor growth . Our finding highlights the potential value of CAFs-derived NRG1 as a novel therapeutic target for osimertinib resistance in lung cancer.
奥希替尼是一种第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）；它在具有EGFR突变的非小细胞肺癌（NSCLC）患者中实现了良好的无进展生存期（PFS），然而，大多数患者会出现耐药，其潜在机制仍有待阐明。癌症相关成纤维细胞（CAFs）是肿瘤微环境中的主要基质细胞。尽管越来越多的证据表明CAFs会导致耐药，但CAFs在NSCLC对奥希替尼耐药中的作用尚未完全明确。在此，我们报道CAFs通过增强NSCLC细胞的干性和减少奥希替尼诱导的凋亡来促进NSCLC细胞对奥希替尼的耐药。CAFs具有高水平的神经调节蛋白-1（NRG1），并且CAFs分泌的NRG1介导了CAFs对奥希替尼耐药的促进作用，这通过应用重组人NRG1（rhNRG1）和NRG1敲低得以证明。我们还发现奥希替尼刺激CAFs分泌NRG1，这可能会进一步增强对奥希替尼的耐药性。进一步研究表明，CAFs通过NRG1介导的HER3/AKT/NF-κB途径促进NSCLC细胞对奥希替尼的耐药。此外，小鼠异种移植研究表明CAFs增强了奥希替尼治疗后的肿瘤生长。我们的发现突出了CAFs来源的NRG1作为肺癌中奥希替尼耐药新治疗靶点的潜在价值。
