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Updated: May 20, 2025

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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Piperlongumine overcomes osimertinib resistance via governing ubiquitination-modulated Sp1 turnover

Ruirui Wang1, Qiang Wang2, Jinzhuang Liao1

  • 1Department of Radiology and.

JCI Insight
|March 24, 2025
PubMed

Insights

Piperlongumine overcomes osimertinib resistance in non-small cell lung cancer (NSCLC) by targeting c-Met. This natural compound re-sensitizes resistant NSCLC cells to osimertinib, offering a new therapeutic strategy.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Non-small cell lung cancer (NSCLC) presents a significant global health challenge, with increasing incidence.
  • Targeted therapies like osimertinib have improved outcomes but acquired drug resistance remains a major obstacle.
  • Cellular mesenchymal-epithelial transition factor (c-Met) overexpression is implicated in osimertinib resistance.

Purpose of the Study:

  • To identify novel therapeutic strategies to overcome osimertinib resistance in NSCLC.
  • To investigate the role of c-Met in osimertinib-resistant NSCLC.
  • To evaluate piperlongumine as a potential agent to reverse osimertinib resistance.

Main Methods:

  • Screening of a natural product library to identify compounds overcoming osimertinib resistance.
  • In vitro and in vivo experiments to assess the efficacy of piperlongumine and osimertinib combination therapy.
  • Investigating the molecular mechanisms of piperlongumine, including its effect on Sp1, RNF4, and c-Met.

Main Results:

  • High c-Met expression was observed in osimertinib-resistant NSCLC cells; c-Met depletion inhibited tumor growth.
  • Piperlongumine was identified as a potent inhibitor of osimertinib resistance.
  • Combined piperlongumine and osimertinib treatment demonstrated significant antitumor effects and restored sensitivity to osimertinib.
  • Piperlongumine promoted Sp1 ubiquitination and degradation via RNF4, leading to c-Met destabilization and apoptosis.

Conclusions:

  • Piperlongumine shows significant potential in overcoming osimertinib resistance in NSCLC.
  • Targeting c-Met destabilization through piperlongumine offers a promising strategy for managing drug-resistant NSCLC.
  • This study provides new insights for developing effective clinical treatments for resistant NSCLC.
Keywords:
Cell biologyLung cancerOncology

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