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Nrf2 as a Therapeutic Target in the Resistance to Targeted Therapies in Melanoma

Marie Angèle Cucci1, Margherita Grattarola1, Chiara Monge2

  • 1Department of Clinical and Biological Science, University of Turin, Corso Raffaello 30, 10125 Turin, Italy.

Antioxidants (Basel, Switzerland)
|June 28, 2023
PubMed

Insights

Targeted therapy resistance in melanoma is a major challenge. This study reveals that the antioxidant regulator Nrf2, controlled by DUB3, drives resistance by upregulating YAP, and inhibiting Nrf2 can restore treatment sensitivity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Targeted therapies like BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) have improved outcomes for metastatic melanoma.
  • Acquired resistance to these therapies remains a significant clinical challenge, with many patients developing resistance within a year.
  • Oxidative stress-related mechanisms are increasingly recognized as key drivers of this acquired resistance.

Purpose of the Study:

  • To investigate the role of Nrf2, a master regulator of antioxidant response, in acquired resistance to BRAFi/MEKi in melanoma.
  • To elucidate the mechanisms regulating Nrf2 activity and its potential cooperation with the oncogene YAP in chemoresistance.
  • To evaluate the therapeutic potential of targeting Nrf2 or its regulators in overcoming targeted therapy resistance.

Main Methods:

  • Utilized established in vitro melanoma models with acquired resistance to BRAFi, MEKi, or dual BRAFi/MEKi.
  • Assessed Nrf2 protein levels and regulation in resistant melanoma cells.
  • Investigated the role of the deubiquitinase DUB3 in controlling Nrf2 protein stability.
  • Examined the relationship between Nrf2 and the oncogene YAP expression.
  • Evaluated the effect of Nrf2 or DUB3 inhibition on restoring sensitivity to targeted therapies.

Main Results:

  • Nrf2 was found to be upregulated at the post-translational level in melanoma cells resistant to targeted therapy.
  • The deubiquitinase DUB3 was identified as a key regulator of Nrf2 protein stability in resistant cells.
  • Nrf2 was shown to control the expression of the oncogene YAP.
  • Inhibition of Nrf2, either directly or by targeting DUB3, effectively reverted acquired resistance to BRAFi/MEKi.
  • These findings highlight a novel mechanism of resistance involving Nrf2 and YAP.

Conclusions:

  • Nrf2 plays a critical role in mediating acquired resistance to BRAFi/MEKi in melanoma, partly through the regulation of YAP.
  • DUB3 is a key factor in stabilizing Nrf2, contributing to the resistant phenotype.
  • Targeting the Nrf2/DUB3/YAP axis represents a promising therapeutic strategy to overcome resistance to targeted melanoma therapies.
Keywords:
A375 cell lineBRAFi/MEKiD4M cell lineDUB3Nrf2YAPdabrafenibmelanomatargeted therapy resistancetrametinib

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