吉非替尼是一种表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），是治疗非小细胞肺癌（NSCLC）的关键支柱。然而，获得性耐药仍然是其临床应用的一个挑战，为此，需要逆转非小细胞肺癌吉非替尼耐药的实用策略。铁死亡是一种由铁蛋白依赖性脂质过氧化驱动的程序性细胞死亡，涉及 NSCLC 进展和相关化疗耐药。在我们前期的工作中，自行合成的EGFR抑制剂Yfq07（N4，N6-二取代嘧啶-4,6-二胺衍生物）在体外和体内均对NSCLC表现出显着的抑制作用。在此，我们观察到 Yfq07 抑制 PC-9GR 和 HCC827GR 细胞（两种吉非替尼耐药 NSCLC 细胞系）的增殖。从机械角度来看，Yfq07 抑制 Discoidin 结构域受体 1 (DDR1) 的磷酸化，这是一种在多种癌症中高度表达的受体酪氨酸激酶 (RTK)，同时伴有 miR-3648 下调和 SOCS2 上调。抑制或敲除DDR1可抑制吉非替尼耐药的NSCLC细胞的增殖、迁移和侵袭，另一方面也下调miR-3648并促进SOCS2表达。更具体地说，miR-3648靶向SOCS2 mRNA的3'UTR片段，从而影响P-ERK信号通路来调节吉非替尼耐药的NSCLC细胞的恶性行为。此外，Yfq07还通过SOCS2触发xCT-GPX4通路的抑制间接诱导吉非替尼耐药的NSCLC细胞的铁死亡。总之，我们的研究表明DDR1抑制剂Yfq07通过DDR1-miR-3648-SOCS2信号通路促进NSCLC的铁死亡并逆转吉非替尼耐药，这为吉非替尼耐药NSCLC的靶向治疗和针对铁死亡的药物开发提供了见解。版权所有©2024 Elsevier B.V. 保留所有权利。

Gefitinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which serves the critical pillar for the treatment of non-small cell lung cancer (NSCLC). However, the acquired resistance remains a challenge for its clinical application, for which, practical strategies to reverse gefitinib resistance in NSCLC are necessary. Ferroptosis, a programmed cell death driven by ferritin-dependent lipid peroxidation, involves in NSCLC progression and related chemoresistance. In our previous work, the self-synthesised EGFR inhibitor Yfq07 (N4, N6-disubstituted pyrimidine-4,6-diamine derivatives) displayed a considerable inhibitory effect on NSCLC both in vitro and in vivo. Herein, we observed that Yfq07 suppressed the proliferation of PC-9GR and HCC827GR cells, two gefitinib resistance NSCLC cell lines. Mechanically, Yfq07 inhibited the phosphorylation of the Discoidin Domain Receptor 1 (DDR1), a receptor tyrosine kinase (RTK) highly expressed in multiple cancers, accompanied by downregulated miR-3648 and upregulated SOCS2. Inhibition or knockdown of DDR1 suppressed the proliferation, migration, and invasion of gefitinib-resistant NSCLC cells, and on the other hand, also downregulated miR-3648 and promoted SOCS2 expression. More specifically, miR-3648 targeted the 3'UTR segment of SOCS2 mRNA and thus affecting the P-ERK signalling pathway to regulate the malignant behaviors of gefitinib-resistant NSCLC cells. Furthermore, Yfq07 also indirectly induced the ferroptosis of gefitinib-resistant NSCLC cells via SOCS2 triggered inhibition of xCT-GPX4 pathway. In conclusion, our study indicates that DDR1 inhibitor Yfq07 promotes ferroptosis and reverses gefitinib-resistance of NSCLC through DDR1-miR-3648-SOCS2 signalling pathway, which provides insights for targeted therapy of gefitinib-resistant NSCLC and drug developments targeting ferroptosis.Copyright © 2024 Elsevier B.V. All rights reserved.