Mishra Vasudha, Singh Alka, Korzinkin Michael, Cheng Xiangying, Wing Claudia, Sarkisova Viktoria, Koppayi Ashwin L, Pogorelskaya Alexandra, Glushchenko Oksana, Sundaresan Manu, Thodima Venkat, Carter Jack, Ito Koichi, Scherle Peggy, Trzcinska Anna, Ozerov Ivan, Vokes Everett E, Cole Grayson, Pun Frank W, Shen Le, Miao Yuxuan, Pearson Alexander T, Lingen Mark W, Ruggeri Bruce, Rosenberg Ari J, Zhavoronkov Alex, Agrawal Nishant, Izumchenko Evgeny
Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, IL, USA.
Insilico Medicine, Hong Kong, China.
J Exp Clin Cancer Res. 2025 Jan 11;44(1):11. doi: 10.1186/s13046-024-03270-x.
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.
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.
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 by downregulation of genes associated with ACC tumorigenesis, including MYB and MYC (the recognized drivers of ACC progression). Furthermore, as a subset of genes targeted by lenvatinib is upregulated in ACC, we demonstrate that addition of lenvatinib enhanced the growth inhibitory effect of PRMT5 blockade in vitro, suggesting a potential clinical benefit for patients expressing lenvatinib favorable molecular profile.
Taken together, our study underscores the role of PRMT5 in ACC oncogenesis and provides a strong rationale for the clinical development of PRMT5 inhibitors as a targeted monotherapy or combination therapy for treatment of patients with this rare disease, based on the analysis of their underlying molecular profile.
腺样囊性癌（ACC）是一种罕见的腺性恶性肿瘤，通常起源于头颈部的唾液腺。鉴于其生长缓慢，ACC通常在晚期才被诊断出来。ACC的治疗仅限于手术和/或辅助放疗，这往往无法预防疾病复发，而且目前尚无美国食品药品监督管理局（FDA）批准的靶向治疗方法。因此，识别ACC特有的新治疗靶点对于改善患者预后至关重要。
在全面评估了表征ACC的基因表达和信号模式后，我们将PandaOmics（一个用于发现新型治疗靶点的人工智能驱动软件平台）应用于87例原发性ACC的独特转录组数据集。将蛋白精氨酸甲基转移酶5（PRMT5）确定为药物可及性得分最高的假定候选靶点后，我们接下来使用ACC细胞系、类器官和患者来源的异种移植（PDX）模型确定PRMT5抑制剂（PRT543和PRT811）的适用性。然后分析了与PRMT5抑制反应相关的分子变化以及与乐伐替尼联合治疗的抗增殖作用。
使用综合的人工智能驱动引擎进行靶点识别，PRMT5在ACC的潜在治疗靶点候选物中被预测出来。我们在此表明，在几种ACC细胞和动物模型中，选择性PRMT5抑制剂单药治疗诱导了强大的抗肿瘤活性，同时与ACC肿瘤发生相关的基因（包括MYB和MYC，公认的ACC进展驱动因子）表达下调。此外，由于乐伐替尼靶向的一部分基因在ACC中上调，我们证明添加乐伐替尼可增强PRMT5阻断在体外的生长抑制作用，这表明对于具有乐伐替尼有利分子特征的患者可能具有临床益处。
综上所述，我们的研究强调了PRMT5在ACC肿瘤发生中的作用，并基于对其潜在分子特征的分析，为PRMT5抑制剂作为这种罕见疾病患者的靶向单药治疗或联合治疗的临床开发提供了有力依据。
