Establishment of patient-derived xenograft models of adenoid cystic carcinoma to assess pre-clinical efficacy of combination therapy of a PI3K inhibitor and retinoic acid.

Due to the difficulties and long periods of establishment, preclinical animal models of adenoid cystic carcinoma (ACC) are scarce but imperative. The researches involving molecular features and therapeutic targets of ACC require an integrated group of preclinical animal models which can credibly retain the heterogeneity of this tumor. Currently chemotherapies and targeting therapies have modest efficacy in ACC and the overall response rate is rather low. Therefore, novel therapeutic regimen of ACC is urgently needed and remains a major clinical challenge. We transplanted a group of tumor samples from human salivary ACC into immunodeficient mice to establish patient-derived xenografts (PDXs). Patient tumors and their matched PDXs were conducted histological analyses, whole-exome sequencing (WES) and RNA-seq respectively. 13 PDXs were successfully established from 34 ACC, involved in 3 histological types, including cribriform, tubular, and solid. These ACC PDXs generally reflected the histopathological and molecular features of their corresponding original tumors. MYB/MYBL1-NFIB fusion (53.85%) and high-frequency mutation genes, such as KDM6A, KMT2C, KMT2D, NOTCH1, NOTCH2, SMARCA4 and PIK3CA were mainly conserved in PDXs. Guided by the genetic alterations, the efficiencies of retinoic acid (RA) and a PI3K inhibitor were evaluated in ACC PDX models harboring both MYB fusion and PIK3CA amplification/mutation. Combination treatment of the PI3K inhibitor and RA demonstrated remarkable inhibition of tumors in PDXs harboring both PIK3CA mutation/amplification and MYB-NFIB fusion gene in vivo and in vitro. In this study, we displayed the morphologically and genetic featured PDXs which recapitulated the heterogeneity of original ACC tumors, indicating that the models could be used as a platform for drug screening for therapy response. The feasibility of combination treatment approaches for dual targets were confirmed, providing new regimens for personalized therapies in ACC.