Abstract 1651: Targeting intermediates of the PRMT5/BRG1 axis as a combination therapy

Abstract

Abstract Over 40% of colorectal cancer (CRC) patients harbor a mutation in the KRAS gene, leading to a worse prognosis. PRMT5 and BRG1 are proteins considered potential therapeutic targets for cancer. Our lab has previously reported that both PRMT5 and BRG1 are overexpressed in KRAS mutant CRC when compared to KRAS wild-type CRC. It is therefore proposed that the PRMT5-BRG1 axis may be a strong therapeutic target for CRC. In this study, several key proteins that potentially mediate crosstalk between the PRMT5-BRG1 axis and KRAS were investigated.A literature review was first conducted to determine how the PRMT5-BRG1 axis acts in cancers. Additionally, pathways that may be involved in mediating the potential crosstalk between BRG1 and KRAS were discussed. Initial findings indicated that the PRMT5-BRG1 axis facilitates cancer oncogenesis. At the same time, the axis suppresses Myc/Max/Mad expression, leading to a dual role of the PRMT5-BRG1 axis depending on the tumor status. BRG1 was also found to work alongside mutant KRAS to affect tumor levels, with the effect differing by tumor type. The STRING database to determine the connection between the PRMT5-BRG1 axis and KRAS. It was determined that PRMT5, BRG1, and KRAS all interact with PBRM1, SMARCB1, ARID1A, and ARID2, with a combined interaction score >0.5. The UCSC Xena software was then used to analyze the mRNA data of CRC patients from The Cancer Genome Atlas (TCGA) database. Xena was utilized to determine which proteins are over expressed in CRC patient tumor samples compared to non-cancerous colon and rectum patient samples. Levels of PBRM1 and ARID1A were observed to significantly decrease in CRC patients as compared to non-cancerous samples by approximately 15% (adjp < 0.0001 and 0.05, respectively). However, SMARCB1 expression increased by 12% (adjp < 0.05). The Gene Expression Profiling Interactive Analysis (GEPIA) software was then used to analyze the correlation between the intermediary genes and PRMT5, BRG1, and KRAS in CRC patient tumor samples. PBRM1, SMARCB1, ARID1A, and ARID2 all demonstrated positive correlation with PRMT5, SMARCA4, and KRAS (R greater than 0.75 for nearly all correlations and p =0) in CRC patient tumor samples. Our study thus showcases the possible disrepair of the PRMT5/BRG1 axis in relation to KRAS. Key downstream proteins are decreased in CRC and may lower the potential crosstalk between PRMT5, BRG1, and KRAS. These findings are significant, and these key intermediate proteins may be strong therapeutic targets via inducing expression. Further research is currently in progress to outline the molecular processes behind the therapeutic role of revitalizing the SMARCA4/BRG1 axis when the downstream proteins are induced. Citation Format: Aaron Shaykevich, Isaac Silverman, Alexander Siegman, Radhashree Maitra. Targeting intermediates of the PRMT5/BRG1 axis as a combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1651.