YAP1 drives aggressive and therapy resistant state in melanoma through reprogramming the chromatin and regulating...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• BRAF/MEK inhibitors show promise but face resistance in ~50% of melanoma patients.
• Understanding resistance mechanisms is crucial for improving melanoma treatment outcomes.

Purpose of the Study:

• To investigate the role of YAP1 in BRAF/MEK inhibitor resistance in metastatic melanoma.
• To identify therapeutic strategies targeting YAP1-mediated resistance.

Main Methods:

• Correlating YAP1 activation with survival in metastatic melanoma.
• Investigating YAP1's interaction with BRD4 and TEAD in chromatin remodeling.
• Analyzing clinical biopsies for YAP1 target gene expression.
• Evaluating pharmacological inhibition of BRD4/TEAD in preclinical models.
• Assessing the synergy of TEAD inhibitors with immune checkpoint blockade in vivo.

Main Results:

• Robust YAP1 activation in metastatic melanoma correlates with poor survival.
• YAP1, with BRD4 and TEAD, remodels chromatin to sustain oncogenic signaling and resistance.
• YAP1 target gene expression is elevated in resistant melanoma biopsies.
• Inhibition of BRD4 or TEAD reduces YAP1 transcription and reactivates antitumor immunity.
• TEAD inhibitors synergize with immune checkpoint blockade, increasing CD8+ T cell infiltration and survival in a melanoma mouse model.

Conclusions:

• YAP1 activation is a key driver of BRAF/MEK inhibitor resistance in melanoma via chromatin remodeling.
• Targeting TEAD specifically presents a promising dual strategy to overcome resistance and enhance anti-tumor immunity.
• TEAD inhibitors offer a novel therapeutic avenue for BRAF/MEK inhibitor-resistant melanoma.