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

Adenoid cystic carcinoma (ACC), a rare salivary glands malignancy, is characterized by unpredictable andaggressive long-term behavior. With limited efficacy of systemic treatment and no FDA-approved targetedagents, ACC remains a difficult disease to treat. Applying an innovative AI-driven target discovery platform on the transcriptomic dataset of primary ACCs, we identified protein arginine methyltransferase PRMT5 as a putative therapeutic candidate with the top-scored druggability. Here we show that monotherapy with selective PRMT5 inhibitors (PRT545 and PRT811) induces a potent anti-tumor activity in ACC cell lines, organoids, and PDX models, paralleled by downregulation of genes associated with ACC tumorigenesis, including MYB and MYC. Furthermore, we demonstrate that lenvatinib enhances growth inhibitory effect of PRMT5 blockade in vitro, suggesting a potential clinical benefit for patients expressing lenvatinib favorable molecular profile. Our study provides a strong rationale for the clinical development of PRMT5 inhibitors as a targeted monotherapy or combination therapy for ACC.In this study, transcriptomic analysis was conducted using the Illumina NovaSeq 6000 platform on sixty-two primary ACC formalin-fixed paraffin-embedded (FFPE) samples and 16 matching normal salivary tissue specimens (adjacent non-involved tissues free of atypical cells).