The ERK1/2 (RAS, RAF, MEK, ERK) and PI3K (PI3K, AKT, mTOR, PTEN) pathways are the chief signaling pathways for cellular proliferation, survival, and differentiation. Overactivation and hyperphosphorylation of the ERK1/2 & PI3K pathways is frequently observed in cancer and is associated with poor patient prognosis. While it is well known that genetic alterations lead to the dysregulation of the ERK1/2 & PI3K pathways, increasing evidence showcase that epigenetic alterations also play a major role in the regulation of the ERK1/2 & PI3K pathways. Protein Arginine Methyltransferase 5 (PRMT5) is a posttranslational modifier for multiple cellular processes, which is currently being tested as a therapeutic target for cancer. PRMT5 has been shown to be overexpressed in many types of cancers, as well as negatively correlated with patient survival. Numerous studies are indicating that as a posttranslational modifier, PRMT5 is extensively involved in regulating the ERK1/2 & PI3K pathways. In addition, a large number of in vitro and in vivo studies are demonstrating that PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, show significant therapeutic effects in many cancer types. In this review, we explore the vast interactions that PRMT5 has with the ERK1/2 & PI3K pathways, and we make the case for further testing of PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, for the treatment of cancer.

Nearly 45% of colorectal cancer (CRC) patients harbor a mutation in their KRAS gene for which, despite many years of research, there are still no targeted therapies available. Protein Arginine Methyltransferase 5 (PRMT5) is a transcription regulator for multiple cellular processes that is currently being tested as a potential target in several cancer types. PRMT5 has been previously shown to be overexpressed in approximately 75% of CRC patient tumor samples, as well as negatively correlated with CRC patient survival. Here, we provide evidence that PRMT5 can act as a surrogate target for mutated KRAS in CRC. Our findings show that PRMT5 expression is upregulated, as well as positively correlated with KRAS expression, in CRC patient datasets. Moreover, our results reveal that PRMT5 is further overexpressed in KRAS mutant CRC cells when compared to KRAS wild type (WT) CRC cells at both the transcriptional and translational levels. Additionally, our data demonstrate that this further overexpression of PRMT5 in the KRAS mutant CRC cells affects an even greater degree of growth inhibition, apoptosis, and cell cycle arrest, following treatment with PRMT5 inhibitor, when compared to the KRAS WT CRC cells. Our research therefore suggests for the first time that PRMT5 and KRAS may crosstalk, and thus, PRMT5 can potentially be used as a surrogate target for mutated KRAS in CRC.

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide with KRAS mutations present in nearly 45% of cases. Compared to KRAS wild-type (WT) CRC, KRAS-mutant CRC is associated with poorer prognosis and fewer effective treatment options. Protein Arginine Methyltransferase 5 (PRMT5), an epigenetic regulator involved in diverse cellular processes, is currently under investigation as a therapeutic target in multiple cancer types. Our previous work demonstrated that PRMT5 inhibition produces stronger therapeutic effects in KRAS-mutant CRC cells than in KRAS WT cells, suggesting potential crosstalk between PRMT5 and KRAS. In this study, we aimed to identify key downstream proteins that may mediate this interaction. Through a literature review, protein–protein interaction analysis (STRING database), gene expression analysis (GEPIA database), and correlation analysis (GEPIA database), we identified MYC, E2F1, and EIF4E as critical candidates. These proteins are shown to interact with both PRMT5 and KRAS in STRING, are overexpressed in CRC tumor samples, and show positive gene expression correlations with PRMT5 and KRAS in patient data. These findings are significant, as they provide new insights into the PRMT5–KRAS crosstalk and suggest potential targets for novel and combination therapies in KRAS-mutant CRC. Further research and biological experiments are needed to verify and outline the exact molecular processes behind MYC, E2F1, and EIF4E’s interactions with both PRMT5 and KRAS.

The ERK1/2 and PI3K pathways are the chief signaling pathways for cellular proliferation, survival, and differentiation. Overactivation of the ERK1/2 & PI3K pathways is commonly seen in cancer and is associated with poor patient prognosis. Increasing evidence is showcasing that epigenetic alterations play a major role in regulating the ERK1/2 & PI3K pathways. Protein Arginine Methyltransferase 5 (PRMT5) is an epigenetic regulator currently undergoing clinical trials as a potential therapeutic target for cancer. PRMT5 has been shown to be overexpressed and negatively correlated with patient survival in many types of cancers. Recent studies are indicating that PRMT5 is involved in regulating the ERK1/2 & PI3K pathways. Moreover, our group's work, as well as other studies, are demonstrating that PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, show significant therapeutic effects in many types of cancers. In this study, the Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the RNA-Seq data of colorectal cancer (CRC) patients from The Cancer Genome Atlas (TCGA) database. We first used the GEPIA database to determine which proteins in the ERK1/2 & PI3K pathways are expressionally correlated with PRMT5 in colon and rectum patient tumor samples. We found that the receptor proteins EGFR and FGFR3 were positively correlated with PRMT5 with a R-Value > 0.61 and a P-Value < 0.01. We further determined that the ERK1/2 pathway proteins KRAS, RAF, MEK, and ERK were all positively correlated with PRMT5 with a R-Value > 0.73 and a P-Value < 0.01. Lastly, we found that the PI3K pathway proteins PI3K, AKT, mTOR, and PTEN were positively correlated with PRMT5 with a R-Value > 0.71 and a P-Value < 0.01. We next used the STRING database to analyze and determine which proteins in the ERK1/2 & PI3K pathways interact with PRMT5. We found that PRMT5 interacts with the receptor proteins EGFR and FGFR3, the ERK1/2 pathway proteins KRAS, and lastly, the PI3K pathway proteins AKT, mTOR, and PTEN with an interaction score > 0.150. Finally, we then used Biorender to develop a protein network map to model the proteins in the ERK1/2 & PI3K pathways that both positively correlate with, as well as interact with, PRMT5. Our protein network map demonstrates that PRMT5 is positively correlated with (R-Value > 0.61, P-Value < 0.01), as well as interacts with (interaction score > 0.150) the following ERK1/2 & PI3K pathway proteins: EGFR, FGFR3, KRAS, AKT, mTOR, and PTEN. Our study thus shows further evidence that PRMT5 is positively correlated with, as well as interacts with, the ERK1/2 & PI3K pathways in CRC. These findings are significant as they make the case for additional testing of PRMT5 inhibition, as well as PRMT5 and ERK1/2 & PI3K combination therapies, for the treatment of cancer. Further analysis is currently in progress to delineate the molecular mechanisms behind PRMT5’s interactions with the ERK1/2 & PI3K pathways. Citation Format: David Shifteh, Tzuriel Sapir, Moshe Pahmer, Sanjay Goel, Radhashree Maitra. PRMT5 is positively correlated with and interacts with the ERK1/2 & PI3K Pathways in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3369.

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States. Recent breakthroughs in research are highlighting the complex genetic and epigenetic alterations driving CRC progression. Among these, the ERK1/2 and PI3K pathways are central regulators of cellular proliferation, survival, and differentiation. The overactivation of these pathways is frequently observed in cancer and is associated with poor patient prognosis. Protein Arginine Methyltransferase 5 (PRMT5), a key epigenetic regulator, has been implicated in modulating the ERK1/2 and PI3K pathways in cancer. Previous studies, including those from our own group, are starting to suggest that targeting PRMT5 and the ERK1/2 and PI3K pathways may offer therapeutic benefits. Thus, we sought to provide further evidence of the relationship between PRMT5 and the ERK1/2 and PI3K pathways in CRC. Using patient tumor gene expression data and protein–protein interaction networks, we provide further evidence that PRMT5 is positively correlated with, and interacts with, the ERK1/2 and PI3K pathways in CRC. These findings are significant, as they further strengthen the case for the urgent need of additional research into therapeutic strategies targeting PRMT5 and the ERK1/2 and PI3K pathways in CRC.