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HDAC6-mediated EGFR stabilization and activation restrict cell response to sorafenib in non-small cell lung cancer

Zhihao Wang1,2, Pengchao Hu3, Fang Tang1,2

  • 1Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, People's Republic of China.

Medical Oncology (Northwood, London, England)
|April 20, 2016
PubMed

Insights

Sorafenib fails to improve survival in advanced non-small cell lung cancer (NSCLC) because it stabilizes epidermal growth factor receptor (EGFR). Inhibiting histone deacetylase 6 (HDAC6) overcomes this resistance, improving sorafenib efficacy in NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Sorafenib, a multi-targeted kinase inhibitor, has shown limited efficacy in advanced non-small cell lung cancer (NSCLC).
  • The underlying molecular mechanisms for sorafenib's failure to improve overall survival in NSCLC remain unclear.
  • Understanding resistance mechanisms is crucial for improving therapeutic strategies in NSCLC.

Purpose of the Study:

  • To elucidate the molecular mechanisms behind sorafenib's inefficacy in advanced NSCLC.
  • To investigate the role of epidermal growth factor receptor (EGFR) pathway activation in sorafenib resistance.
  • To explore the potential of targeting histone deacetylase 6 (HDAC6) to enhance sorafenib's effectiveness in NSCLC.

Main Methods:

  • Investigated the effect of sorafenib on EGFR and its associated pathways in NSCLC cells.
  • Assessed the role of histone deacetylase 6 (HDAC6) in regulating EGFR stability and degradation.
  • Evaluated the synergistic effect of sorafenib combined with HDAC6 inhibitors in NSCLC cell models.

Main Results:

  • Sorafenib treatment leads to the stabilization of epidermal growth factor receptor (EGFR) and subsequent activation of the EGFR pathway.
  • Histone deacetylase 6 (HDAC6) stabilization partially mediates sorafenib-induced EGFR pathway activation and confers resistance.
  • Overexpression of HDAC6 enhances resistance to sorafenib in NSCLC cells.
  • Inhibition of HDAC6 synergizes with sorafenib to induce NSCLC cell death by blocking sorafenib-mediated EGFR pathway activation.

Conclusions:

  • Sorafenib-induced EGFR pathway activation, partly mediated by HDAC6 stabilization, contributes to its limited efficacy in advanced NSCLC.
  • Targeting HDAC6 in combination with sorafenib presents a potential strategy to overcome resistance and improve treatment outcomes in NSCLC.
  • These findings may offer insights into the failure of previous sorafenib trials and guide future therapeutic development for NSCLC.
Keywords:
EGFRHDAC6NSCLCSorafenib

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