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Gefitinib-induced epidermal growth factor receptor-independent keratinocyte apoptosis is mediated by the JNK

P-H Lu1, T-C Kuo, K-C Chang

  • 1Department of Dermatology, Taipei City Hospital, Zhongxiao Branch, Taipei, Taiwan.

The British Journal of Dermatology
|September 18, 2010
PubMed
Abstract

Insights

Gefitinib causes skin toxicity through a pathway independent of epidermal growth factor receptor (EGFR) inhibition. This toxicity involves the activation of JNK signaling, leading to keratinocyte apoptosis.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • Gefitinib (ZD1839) is a targeted therapy inhibiting epidermal growth factor receptor (EGFR) tyrosine kinase, effective against various cancers.
  • Skin toxicity is a common side effect of gefitinib, often linked to EGFR pathway inhibition.
  • Potential EGFR-independent mechanisms contributing to gefitinib-induced skin toxicity require investigation.

Purpose of the Study:

  • To elucidate EGFR-independent mechanisms underlying gefitinib-induced skin toxicity.
  • To investigate the role of specific signaling pathways in gefitinib's effects on keratinocytes.

Main Methods:

  • Utilized HaCaT keratinocytes and A549/PC9 lung cancer cells treated with gefitinib.
  • Assessed cell viability via MTT assay following EGFR gene silencing.
  • Analyzed signaling pathways using immunoblotting and evaluated keratinocyte apoptosis through nuclear condensation and flow cytometry.

Main Results:

  • Gefitinib exhibited cytotoxicity in HaCaT cells even after EGFR gene silencing, confirming an EGFR-independent mechanism.
  • Gefitinib dose-dependently increased phosphorylation of p38 MAPK and JNK in HaCaT cells.
  • Inhibition of JNK signaling attenuated gefitinib-induced cytotoxicity and apoptosis; increased phosphorylated JNK was observed in patient skin lesions.

Conclusions:

  • Gefitinib induces keratinocyte apoptosis via an EGFR-independent pathway.
  • JNK activation is a key mechanism in gefitinib-induced skin toxicity.

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