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BET inhibitors synergize with sunitinib in melanoma through GDF15 suppression

Furong Zeng1,2,3,4, Yayun Li1,3,4, Yu Meng1,3,4

  • 1Department of Dermatology, Hunan Engineering Research Center of Skin Health and Disease, Hunan Key Laboratory of Skin Cancer and Psoriasis, Xiangya Clinical Research Center for Cancer Immunotherapy, Xiangya Hospital, Central South University, Changsha, Hunan, China.

Experimental & Molecular Medicine
|January 31, 2023
PubMed

Insights

Combining BET inhibitors with sunitinib effectively kills melanoma cells by inducing apoptosis and cell cycle arrest. This combination therapy targets GDF15 expression, offering a promising new strategy for melanoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Targeting bromodomain and extra-terminal domain (BET) proteins is a promising strategy for melanoma treatment.
  • Developing novel therapeutic combinations can enhance melanoma cell killing.
  • Identifying synergistic drug combinations is crucial for new clinical applications.

Purpose of the Study:

  • To identify FDA-approved drugs that synergize with BET inhibitors in melanoma.
  • To elucidate the mechanisms underlying the synergistic effects of BET inhibitors and sunitinib.
  • To evaluate the efficacy of the combination therapy in vivo.

Main Methods:

  • Drug synergy screening using a library of 240 FDA-approved drugs combined with JQ1 (a BET inhibitor).
  • Assessment of apoptosis and cell cycle arrest in melanoma cells treated with combination therapy.
  • Investigation of Growth Differentiation Factor 15 (GDF15) expression regulation by BET proteins (BRD4) and the IL6/STAT3 axis.
  • Xenograft assays to evaluate in vivo efficacy.

Main Results:

  • Sunitinib was identified as a drug that synergizes with BET inhibitors in melanoma cells.
  • The combination of BET inhibitors and sunitinib induced apoptosis and cell cycle arrest.
  • BET inhibitors sensitized melanoma cells to sunitinib by inhibiting GDF15 expression.
  • GDF15 was shown to be regulated by BRD4 directly or via the BRD4/IL6/STAT3 pathway.
  • Combination therapy demonstrated significant melanoma suppression in vivo.

Conclusions:

  • BET inhibitors synergize with sunitinib to enhance anti-melanoma effects.
  • Inhibition of GDF15 expression is a key mechanism mediating this synergy.
  • The BRD4/IL6/STAT3 axis plays a role in regulating GDF15.
  • This combination therapy represents a potential new treatment strategy for melanoma.

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