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Acetaldehyde dehydrogenase 1A1 upregulation drives dacomitinib-induced skin toxicity through mitochondrial

Wanying Zhou1, Xinyue Ma1, Lili Tan1

  • 1Postgraduate training base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310022, China.

Cellular Signalling
|June 5, 2025
PubMed

Insights

Dacomitinib causes skin toxicity by damaging keratinocytes via the ALDH1A1 enzyme. Targeting ALDH1A1 may prevent or treat this side effect in non-small cell lung cancer patients.

Area of Science:

  • Oncology
  • Dermatology
  • Molecular Biology

Background:

  • Dacomitinib, a pan-human epidermal growth factor receptor (HER) tyrosine kinase inhibitor (TKI), treats EGFR-mutated non-small cell lung cancer (NSCLC).
  • Cutaneous toxicity limits dacomitinib use, with unknown mechanisms hindering targeted interventions.

Purpose of the Study:

  • To investigate the mechanism of dacomitinib-induced skin toxicity.
  • To identify potential therapeutic targets for mitigating dacomitinib's cutaneous side effects.

Main Methods:

  • Established an animal model for dacomitinib-induced cutaneous toxicity.
  • Analyzed dacomitinib's effects on keratinocyte mitochondrial function, apoptosis, and inflammatory factor secretion.
  • Investigated the role of the retinoid pathway and acetaldehyde dehydrogenase 1A1 (ALDH1A1) in toxicity.
  • Assessed the therapeutic potential of ALDH1A1 knockdown and silibinin treatment.

Main Results:

  • Dacomitinib induced mitochondrial dysfunction, apoptosis, and inflammation in keratinocytes.
  • Dacomitinib activated the retinoid pathway, upregulating ALDH1A1, a key factor in skin toxicity.
  • ALDH1A1 knockdown ameliorated dacomitinib-induced keratinocyte damage.
  • Silibinin reduced dacomitinib-induced cutaneous toxicity by downregulating ALDH1A1.

Conclusions:

  • ALDH1A1 plays a critical role in dacomitinib-induced cutaneous toxicity.
  • ALDH1A1 represents a potential therapeutic target for managing dacomitinib's skin side effects in NSCLC patients.
Keywords:
ALDH1A1ApoptosisCutaneous toxicityDacomitinibMitochondrial dysfunctionSilibinin

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