2. Academic Validation
  3. Inhibition of DDR1 promotes ferroptosis and overcomes gefitinib resistance in non-small cell lung cancer

Inhibition of DDR1 promotes ferroptosis and overcomes gefitinib resistance in non-small cell lung cancer

  • Biochim Biophys Acta Mol Basis Dis. 2024 Oct;1870(7):167447. doi: 10.1016/j.bbadis.2024.167447.
Yuan Zhang 1,  Jinheng Qian 1,  Yanneng Fu 1,  Zihan Wang 2,  Wanping Hu 3,  Jinxia Zhang 1,  Yuexuan Wang 4,  Yangyang Guo 1,  Weikang Chen 3,  Yejun Zhang 5,  Xuebao Wang 1,  Zixin Xie 1,  Hui Ye 6,  Faqing Ye 7,  Zhigui Zuo 8
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 2 Department of Oral Implantology, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, China.
  • 3 Department of Colorectal Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 4 Laocheng District, Luoyang Maternal and child health family planning service center, Laocheng, Luoyang, Henan 471000, China.
  • 5 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
  • 6 School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: wmcyh@wmu.edu.cn.
  • 7 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: yfq664340@163.com.
  • 8 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China; Department of Colorectal Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. Electronic address: zuozhigui@wmu.edu.cn.
PMID: 39089636 DOI: 10.1016/j.bbadis.2024.167447
Abstract

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.

Keywords

Discoidin domain receptor 1; Ferroptosis; Gefitinib resistance; Non-small cell lung cancer.

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