Cell-type-specific tumour sensitivity identified with a bromodomain targeting PROTAC in adenoid cystic carcinoma

Area of Science:

• Oncology
• Cancer Biology
• Drug Discovery

Background:

• Salivary gland adenoid cystic carcinoma (ACC) is a rare cancer with few treatment options, limited by a lack of effective preclinical models.
• Existing models often fail to capture the genetic complexity, such as MYB::NFIB translocations, crucial for ACC development.

Purpose of the Study:

• To develop and characterize novel patient-derived xenograft (PDX) and organoid models for ACC.
• To evaluate the efficacy of the bromodomain degrader dBET6 in preclinical ACC models.
• To elucidate the mechanism of action of dBET6 in ACC.

Main Methods:

• Generation of ACC patient-derived xenograft (PDX) and 2D/3D organoid models.
• Assessment of MYB expression and genetic translocations in developed models.
• In vitro and in vivo drug sensitivity testing using dBET6.
• Molecular analysis of protein levels (BRD4, MYB) and gene expression.
• Evaluation of cell-type composition changes in response to treatment.

Main Results:

• Developed ACC PDX and organoid models accurately reflecting primary tumor characteristics, including MYB::NFIB translocations.
• Demonstrated in vitro and in vivo sensitivity of ACC cells to dBET6.
• Observed decreased BRD4 and MYB protein levels and target gene expression upon dBET6 treatment.
• Identified a significant alteration in the myoepithelial and ductal cell populations within tumors treated with dBET6.
• Showed that dBET6 inhibits progenitor cell function, particularly in the myoepithelial population.

Conclusions:

• Novel ACC preclinical models (PDX and organoids) are established, preserving key genetic features.
• The bromodomain degrader dBET6 shows significant therapeutic potential against ACC.
• dBET6 exerts its effect by reducing MYB and BRD4 levels and specifically inhibiting progenitor cell function, particularly in myoepithelial cells.
• Targeting both myoepithelial and ductal cell populations may be crucial for effective ACC treatment.