Cell-type-specific tumour sensitivity identified with a bromodomain targeting PROTAC in adenoid cystic carcinoma.
Salivary gland adenoid cystic carcinoma (ACC) is a rare malignancy with limited treatment options. The development of novel therapies is hindered by a lack of preclinical models. We have generated several ACC patient-derived xenograft (PDX) lines that retain the physical and genetic properties of the original tumours, including the presence of the common MYB/MYBL1-NFIB translocation. Using these PDXs, we have developed the conditions for the generation of 2D and 3D ACC models that retain MYB expression and can be used for drug studies. Using these models, we show in vitro and in vivo sensitivity of ACC cells to the bromodomain degrader, dBET6. Molecular studies show a decrease in BRD4 and MYB protein levels and target gene expression with treatment. The most prominent effect of dBET6 on tumours in vivo was a change in the relative composition of ACC cell types expressing either myoepithelial or ductal markers. We show that dBET6 inhibits the progenitor function of ACC cells, particularly in the myoepithelial marker-expressing population, revealing a cell-type-specific sensitivity. These studies reveal a novel mechanistic impact of bromodomain inhibitors on tumours and highlight the need to impact both cell-type populations for more effective treatments in ACC patients. Overall design: Single cells from a PDX line were injected into the flanks of NSG mice. Once tumours developed, mice were allocated to either receive vehicle or dBET6 via IP injection twice daily. Following short term (4 day) treatment with 5mg/kg of dBET6 or vehicle, tumours were harvested and snap frozen. RNA was extracted from these samples and sequenced.