Abstract 534: PRMT5 inhibition as a therapeutic strategy for KRAS mutant CRC: downstream mediators of the PRMT5-KRAS crosstalk

Abstract

Abstract Despite decades of research, there are still no effective targeted treatments for the nearly 45% of colorectal cancer (CRC) patients harboring a mutation in their KRAS gene. Protein Arginine Methyltransferase 5 (PRMT5) is an epigenetic regulator undergoing clinical trials as a potential therapeutic target for cancer. Our group has previously reported that PRMT5 is overexpressed in KRAS mutant CRC when compared to KRAS wild-type (WT) CRC, and that PRMT5 inhibition exhibited greater therapeutic efficacy in KRAS mutant CRC when compared to KRAS WT CRC. We therefore proposed that PRMT5 may be a strong therapeutic target for KRAS mutant CRC, and that PRMT5 and KRAS may crosstalk. In this study, we investigated several key downstream signal transduction proteins that may be involved in mediating the potential crosstalk between PRMT5 and KRAS. This is important, as these key intermediate proteins may be strong therapeutic targets for inhibition, as well as valuable therapeutic targets for combination therapy along with PRMT5 inhibitors. We first conducted a literature review to determine which key downstream proteins may be involved in mediating the potential crosstalk between PRMT5 and KRAS. Our initial findings indicated that MYC, p65/RELA, TP53, P21/CDKN1A, ELF1, E2F1, and EIF4E may be key downstream proteins involved in mediating the potential crosstalk between PRMT5 and KRAS. We next used the STRING database to determine which of the aforementioned proteins have demonstrated interactions with PRMT5 and KRAS. We found that PRMT5 and KRAS both interact with MYC, p65/RELA, TP53, P21/CDKN1A, E2F1, and EIF4E with an interaction score > 0.150. We then used the Gene Expression Profiling Interactive Analysis (GEPIA) database to analyze the RNA-Seq data of CRC patients from The Cancer Genome Atlas (TCGA) database. We first used the GEPIA database to determine which proteins are overexpressed in CRC patient tumor samples compared to normal colon and rectum patient samples. We observed that MYC, TP53, E2F1, and EIF4E are all over 2-fold overexpressed in CRC patient tumor samples compared to normal colon and rectum patient samples (q < 0.01). We next used the GEPIA database to determine which proteins have an expressional correlation with PRMT5 and KRAS in CRC patient tumor samples. We found that MYC, E2F1, and EIF4E are all positively correlated with PRMT5 and KRAS with an R-Value > 0.70 and a P-Value < 0.01 in CRC patient tumor samples. Our study thus showcases the key downstream signal transduction proteins that may be involved in mediating the potential crosstalk between PRMT5 and KRAS. These findings are significant, as these key intermediate proteins may be strong therapeutic targets for inhibition, as well as strong therapeutic targets for a PRMT5 combination therapy. Additional research is currently underway to outline the molecular processes behind MYC, E2F1, and EIF4E’s interactions with both PRMT5 and KRAS. Citation Format: David Shifteh, Tzuriel Sapir, Moshe Pahmer, Sanjay Goel, Radhashree Maitra. PRMT5 inhibition as a therapeutic strategy for KRAS mutant CRC: downstream mediators of the PRMT5-KRAS crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 534.