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TGF-β1 and TNF-α differentially regulate Twist1 mediated resistance towards BRAF/MEK inhibition in melanoma

Dinoop R Menon1, Christian Wels, Ehsan Bonyadi Rad

  • 1Cancer Biology Unit, Department of Dermatology, Medical University of Graz, Graz, Austria; Center for Medical Research, Medical University of Graz, Graz, Austria.

Pigment Cell & Melanoma Research
|July 16, 2013
PubMed

Insights

Transforming growth factor-beta1 enhances melanoma cell death when combined with BRAF or MEK inhibitors by decreasing Twist1. Tumor necrosis factor-alpha increases drug resistance via Twist1.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Melanoma treatment resistance to BRAF and MEK inhibitors is a significant clinical challenge.
  • Cytokines and transcription factors are implicated in the development of drug resistance.
  • Understanding the molecular mechanisms underlying resistance is crucial for improving therapeutic strategies.

Purpose of the Study:

  • To investigate the role of transforming growth factor-beta1 (TGF-β1) in modulating sensitivity to BRAF and MEK inhibitors in melanoma.
  • To elucidate the downstream molecular targets and signaling pathways involved in TGF-β1-mediated drug resistance.
  • To explore the potential of targeting Twist1 as a strategy to overcome resistance to targeted therapies.

Main Methods:

  • Utilized BRAF-mutant melanoma cell lines.
  • Administered BRAF inhibitor (PLX4032) and MEK inhibitor (GSK1120212) alone and in combination with TGF-β1 or tumor necrosis factor-alpha (TNF-α).
  • Assessed cell death, apoptosis, and Twist1 protein levels through overexpression and silencing experiments.

Main Results:

  • Combined treatment with TGF-β1 and BRAF/MEK inhibitors significantly increased melanoma cell death.
  • This effect was mediated by a regulatory decrease in the antiapoptotic protein Twist1.
  • Overexpression of Twist1 attenuated apoptosis, while silencing aggravated it.
  • Conversely, TNF-α exposure increased Twist1 levels, leading to decreased cell death and enhanced drug resistance.

Conclusions:

  • Twist1 is a critical mediator of drug resistance in BRAF-mutant melanoma.
  • TGF-β1 can sensitize melanoma cells to BRAF/MEK inhibitors by downregulating Twist1.
  • TNF-α promotes drug resistance through increased Twist1 expression.
  • Targeting Twist1 may represent a viable strategy to overcome resistance to BRAF- and MEK-targeted therapies.
Keywords:
BRAFTGF-β1TNF-αTwist1drug resistance

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