Adenoid cystic carcinoma (ACC) is a slow-growing salivary gland malignancy. The frequent occurrence of chromosome t(6;9) translocations, resulting in MYB-NFIB fusions, is a hallmark of ACC. Approximately, 50% of all ACCs studied to date have been shown to express MYB-NFIB chimeric transcripts, suggesting a prominent role in ACC tumorigenicity. However, the potential relevance of chimeric MYB-NFIB proteins in the development and progression of ACC remains poorly understood. To assess the role of MYB-NFIB in ACC development, we generated transgenic mice in which MYB-NFIB is overexpressed in salivary and mammary glands, using a doxycycline-inducible system. Importantly, a subset of these mice developed ACCs, suggesting that MYB-NFIB is an oncogenic driver of ACC. Using this reversible inducible model, we investigated whether MYB-NFIB was required to maintain established tumors. We found that suppression of the MYB-NFIB transgene upon exposure to doxycycline (Dox) promoted a rapid tumor regression. Tumoral volumes decreased by more than 50 % after only 10 days of starting Dox. This reduction in volume was accompanied by a transition towards a more organized cellular structure and a reduction in the number of cells positive for Ki-67 and MYB-NFIB. To identify mechanisms involved in tumor regression, we compared the transcriptomes from biopsies collected from salivary tumors prior to MYB-NFIB suppression with those from the same tumors after Dox-induced regression. We found that tumor regression upregulated immune-related pathways and promoted T cell infiltration. Additionally, several pathways were downregulated by MYB-NFIB suppression; particularly NOTCH signaling, Cyclin D1‐CDK4/6, and Wnt/beta-catenin signaling. We then confirmed, by immunohistochemistry, that tumor biopsies taken before Dox had a higher number of cells positive for Cdk6, CyclinD1, and nuclear beta-catenin. Our results suggest that proteins in these pathways could be used as potential therapeutic targets in MYB-NFIB-driven ACCs.

Citation Format: Vicente Escamilla-Rivera, Yuan Hu, Sungman Cho, Adel El-Naggar, Han Luo, Carlos Caulin. Oncogene addition to MYB-NFIB in adenoid cystic carcinomas induced in transgenic mice [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR07.