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Melanoma cells resistant towards MAPK inhibitors exhibit reduced TAp73 expression mediating enhanced sensitivity to

Elena Makino1, Vanessa Gutmann1, Corinna Kosnopfel1

  • 1Division of Dermatooncology, Department of Dermatology, University of Tübingen, Tübingen, Germany.

Cell Death & Disease
|September 13, 2018
PubMed

Insights

Melanoma patients resistant to targeted therapy show increased sensitivity to platinum drugs like cisplatin. This heightened susceptibility is linked to lower TAp73 expression, suggesting a new treatment approach for resistant melanoma.

Area of Science:

  • Oncology
  • Melanoma Research
  • Cancer Therapeutics

Background:

  • Targeted MAPK signalling pathway inhibitors (MAPKi) are used for metastatic melanoma.
  • Acquired resistance to MAPKi leads to disease relapse, necessitating alternative treatments.

Purpose of the Study:

  • To identify alternative therapeutic strategies for melanoma patients with acquired resistance to MAPKi.
  • To investigate the role of TAp73 in mediating sensitivity to platinum-based chemotherapy in MAPKi-resistant melanoma.

Main Methods:

  • Investigated the response of MAPKi-resistant melanoma cells to platinum-based drugs (cisplatin, carboplatin).
  • Assessed the correlation between TAp73 expression levels and drug susceptibility.
  • Examined the impact of TAp73 on DNA double-strand break accumulation and nucleotide excision repair efficiency.

Main Results:

  • Melanoma cells resistant to MAPKi exhibit enhanced susceptibility to cisplatin and carboplatin.
  • This enhanced susceptibility inversely correlates with the expression level of the p53 family member TAp73.
  • Low TAp73 expression in resistant cells reduces nucleotide excision repair, increasing DNA damage from platinum drugs.

Conclusions:

  • Melanoma patients with acquired MAPKi resistance and low TAp73 expression may benefit from platinum-based chemotherapy as a second-line treatment.
  • Targeting TAp73 or leveraging its reduced expression could be a strategy in overcoming MAPKi resistance.

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