PRMT5 inhibition has a potent anti-tumor activity against adenoid cystic carcinoma of salivary glands

作者：Vasudha Mishra, Alka Singh, Michael Korzinkin, Xiangying Cheng, Claudia Wing, Viktoria A. Sarkisova, Ashwin Lakshman Koppayi, Alexandra Pogorelskaya, Oksana E. Glushchenko, Manu Sundaresan, Venkat Thodima, Jack Carter, Koichi Ito, Peggy Scherle, Anna Trzcinska, Ivan V. Ozerov, Everett E. Vokes, Grayson Cole, Frank W. Pun, Le Shen, Yuxuan Miao, Alexander T. Pearson, Mark William Lingen, Bruce Ruggeri, Ari Joseph Rosenberg, Alex Zhavoronkov, Nishant Agrawal, Evgeny Izumchenko · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-024-03270-x · 被引用次数：13 · 研究领域：Cancer-related gene regulation、Virus-based gene therapy research、Axon Guidance and Neuronal Signaling

BACKGROUND: Adenoid cystic carcinoma (ACC) is a rare glandular malignancy, commonly originating in salivary glands of the head and neck. Given its protracted growth, ACC is usually diagnosed in advanced stage. Treatment of ACC is limited to surgery and/or adjuvant radiotherapy, which often fails to prevent disease recurrence, and no FDA-approved targeted therapies are currently available. As such, identification of new therapeutic targets specific to ACC is crucial for improved patients' outcomes. METHODS: After thoroughly evaluating the gene expression and signaling patterns characterizing ACC, we applied PandaOmics (an AI-driven software platform for novel therapeutic target discovery) on the unique transcriptomic dataset of 87 primary ACCs. Identifying protein arginine methyl transferase 5 (PRMT5) as a putative candidate with the top-scored druggability, we next determined the applicability of PRMT5 inhibitors (PRT543 and PRT811) using ACC cell lines, organoids, and patient derived xenograft (PDX) models. Molecular changes associated with response to PRMT5 inhibition and anti-proliferative effect of the combination therapy with lenvatinib was then analyzed. RESULTS: Using a comprehensive AI-powered engine for target identification, PRMT5 was predicted among potential therapeutic target candidates for ACC. Here we show that monotherapy with selective PRMT5 inhibitors induced a potent anti-tumor activity across several cellular and animal models of ACC, which was paralleled ...