Frontiers in Oncology (Apr 2022)

Bruceine H Mediates EGFR-TKI Drug Persistence in NSCLC by Notch3-Dependent β-Catenin Activating FOXO3a Signaling

  • Jiahui Wu,
  • Xiao He,
  • Ziwei Xiong,
  • Lingyu Shi,
  • Daofeng Chen,
  • Yulin Feng,
  • Quan Wen

DOI
https://doi.org/10.3389/fonc.2022.855603
Journal volume & issue
Vol. 12

Abstract

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Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) protein serve as a critical pillar in the treatment of non-small cell lung cancer (NSCLC), but resistance is universal. Identifying the potential key factors of drug resistance to EGFR-TKIs is essential to treat patients with EGFR mutant lung cancer. Our research here shows that bruceine H suppressed the proliferation, migration, and invasion of lung cancer cells; inhibited the growth of human NSCLC cell xenografts; and enhanced the therapeutic effects of gefitinib in the PC-9/GR xenograft models, possibly by inhibiting Notch3. In order to analyze the potential targets of the combination of Notch3 and EGFR-TKIs on resistance to EGFR, we analyzed the differences of gene expression between NSCLC tissues and EGFR-driven gefitinib-resistant tumoral groups and then identify through the WGCNA key genes that may provide therapeutic targets for TKI-resistant lung cancer xenograft models. We confirmed that EGFR-TKI in combination with Notch3 inhibitor can inhibit the expression of β-catenin and enhance the level of FOXO3a, leading to improved recurrence-free survival and overall survival of the xenotransplantation model. These results support that the combination of gefitinib and bruceine H may provide a promising alternative strategy for treating acquired EGFR-TKI resistance in patients with NSCLC.

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