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YAP Upregulation Contributes to Acquired Resistance to BET Inhibitors in Uveal Melanoma

Yan-Ling Zhou1, Xiao-Lian Liu2,3, Si-Si Huang1

  • 1NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Science, Southern Medical University, Guangzhou, China.

Pigment Cell & Melanoma Research
|July 8, 2025
PubMed

Insights

BET inhibitors show promise for uveal melanoma (UM) treatment but resistance emerges. This study reveals YAP activation as a key mechanism of resistance, suggesting YAP inhibition as a potential therapeutic strategy for resistant UM.

Area of Science:

  • Oncology
  • Epigenetics
  • Molecular Biology

Background:

  • BET inhibitors offer a novel epigenetic mechanism for treating malignant tumors.
  • Uveal melanoma (UM) is a rare but aggressive eye cancer.
  • Acquired resistance to BET inhibitors limits their clinical efficacy in UM.

Purpose of the Study:

  • To investigate the mechanisms underlying acquired resistance to BET inhibitors in uveal melanoma.
  • To identify potential therapeutic targets to overcome BET inhibitor resistance in UM.

Main Methods:

  • Development of isogenic OTX015-resistant UM cell models (OMM2.3R and OMM2.5R).
  • Assessment of OTX015 sensitivity and migratory ability in parental and resistant cells.
  • Transcriptome analysis to identify molecular changes in resistant cells.
  • Evaluation of YAP inhibition efficacy in resistant UM cells.

Main Results:

  • Resistant UM cells exhibited reduced sensitivity to OTX015-induced cytotoxicity and migration inhibition.
  • Transcriptome analysis revealed upregulation of YAP-activated genes in resistant cells.
  • OTX015-resistant UM cells remained sensitive to YAP inhibition.

Conclusions:

  • YAP activation is a novel compensatory mechanism driving BET inhibitor resistance in uveal melanoma.
  • Targeting YAP offers a potential therapeutic strategy to overcome BET inhibitor resistance in UM patients.
  • This finding has clinical translational potential for treating resistant UM.
Keywords:
BET inhibitorsYAPdrug resistanceuveal melanomaverteporfin

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