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Pharmacological STING Activation Is a Potential Alternative to Overcome Drug-Resistance in Melanoma

Sandhya Chipurupalli1,2, Raja Ganesan1, S P Dhanabal3

  • 1Cellular-Stress and Immune Response Laboratory, Center for Cancer Biology, University of South Australia, Adelaide, SA, Australia.

Frontiers in Oncology
|June 2, 2020
PubMed

Insights

STING agonists like diABZI can overcome therapy resistance in melanoma. By inhibiting NRF2-dependent antioxidant responses, STING activation sensitizes melanoma cells to BRAF inhibitors, enhancing cell death.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Melanoma exhibits aggressive behavior, with chemotherapy resistance significantly impacting patient outcomes.
  • Cancer cells, including melanoma, utilize NRF2-dependent antioxidant responses to survive oxidative stress and therapy.
  • BRAF inhibitors, a common melanoma treatment, can paradoxically induce NRF2 activity, contributing to resistance.

Purpose of the Study:

  • To investigate whether STING agonists can sensitize melanoma cells to BRAF inhibitors.
  • To determine if STING activation can overcome NRF2-mediated resistance to melanoma therapies.

Main Methods:

  • Utilized a dimeric aminobenzimidazole (diABZI) as a STING agonist.
  • Administered diABZI in combination with clinically used BRAF inhibitors.
  • Assessed NRF2 pathway activity and melanoma cell death.

Main Results:

  • Pharmacological activation of STING by diABZI downregulates NRF2-dependent antioxidant responses.
  • The combination of diABZI and BRAF inhibitors potentiates cell death in melanoma cells.
  • STING activation abrogates the protective function of NRF2 in melanoma.

Conclusions:

  • STING agonists represent a promising strategy to enhance the efficacy of BRAF inhibitors in melanoma treatment.
  • Targeting the STING pathway offers a novel approach to overcome therapy resistance in aggressive skin cancers.
Keywords:
BRAFNRF2STINGdabrafenibdiABZImelanomavemurafenib

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