Protein arginine methyltransferase 5 as a tumor promoter and therapeutic target in gastrointestinal cancers

Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are among the most commonly diagnosed forms of cancer in the United States. Due to their widespread prevalence and high mortality rate, it is vital to develop effective therapeutic drugs to combat these deadly diseases. In both CRC and PDAC, the multifunctional factor nuclear factor kappa B (NF-kB), a central coordinator of immune responses, is activated abnormally, leading to tumorigenesis and cancer progression. Therefore, controlling NF-kB activity is critical in the treatment of these cancers. Previously, we discovered a novel mechanism by which NF-kB is activated through methylation by an epigenetic enzyme known as protein arginine methyltransferase 5 (PRMT5). We showed that overexpression of PRMT5 significantly promoted several characteristics associated with cancer, including increased cell proliferation, migration, and anchorage-independent growth in both CRC and PDAC cells, thus, putting forward PRMT5 as a novel therapeutic target in these cancers. In this study, we successfully adapted AlphaLISA technique into a high-throughput screen platform, and further employed this approach to successfully identify PR5-LL-FDA1 as a potent PRMT5 inhibitor from commercially-available screening libraries. Furthermore, we confirmed that treatment of PDAC and CRC cells with PR5-LL-FDA1 led to decreased NF-kB activation, and reduced cancer associated properties in PDAC and CRC cells. Importantly, we show that PR5-LL-FDA1 is more efficacious than the commercial PRMT5 inhibitor, EPZ015666 in both PDAC and CRC. Our work clearly highlights the significant potential of PRMT5 as a therapeutic target in PDAC and CRC and hold the promise to establish PR5-LL-FDA1 as a promising basis for new drug development in the future. Citation Format: Lakshmi Prabhu, Lan Chen, Ahmad Safa, Murray Korc, Zhong-Yin Zhang, Tao Lu. Protein arginine methyltransferase 5 as a tumor promoter and therapeutic target in gastrointestinal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4862.