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TGFβ2-mediated epithelial-mesenchymal transition and NF-κB pathway activation contribute to osimertinib resistance

Xiao-Ming Jiang1, Yu-Lian Xu1, Luo-Wei Yuan1

  • 1State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China.

Acta Pharmacologica Sinica
|July 18, 2020
PubMed

Insights

Resistance to osimertinib in lung cancer is linked to epithelial-mesenchymal transition (EMT) and activation of the NF-κB pathway. Targeting TGFβ2 may overcome this resistance by inhibiting EMT and NF-κB signaling.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Osimertinib is a key treatment for EGFR-mutant non-small cell lung cancer (NSCLC).
  • Acquired resistance to osimertinib remains a significant clinical challenge.
  • Understanding resistance mechanisms is crucial for developing effective therapies.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying osimertinib resistance in NSCLC cells.
  • To identify potential therapeutic strategies to overcome osimertinib resistance.

Main Methods:

  • Utilized osimertinib-resistant NCI-H1975/OSIR cell lines.
  • Investigated epithelial-mesenchymal transition (EMT) and ferroptosis induction.
  • Analyzed the role of TGFβ2 and the NF-κB pathway.
  • Correlated findings with The Cancer Genome Atlas (TCGA) lung adenocarcinoma data.

Main Results:

  • Osimertinib-resistant cells exhibited EMT, driven by TGFβ2 upregulation and SMAD2 activation.
  • EMT conferred sensitivity to ferroptosis induction via GPX4 inhibition.
  • Resistant cells showed dependency on the NF-κB pathway for survival.
  • Osimertinib-induced NF-κB activation was dependent on TGFβ2.
  • TCGA data showed correlation between TGFB2, EMT genes, and NF-κB pathway.

Conclusions:

  • TGFβ2 plays a dual role in osimertinib resistance by promoting EMT and activating the NF-κB pathway.
  • Combined targeting of TGFβ2, EMT, and NF-κB may offer a strategy to overcome osimertinib resistance.
  • These findings provide novel insights into resistance mechanisms and potential therapeutic avenues for NSCLC.
Keywords:
EGFR mutant non-small cell lung cancerNF-κBTGFβ2epithelial-mesenchymal transitionosimertinib resistance

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