Introduction

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 therapeutic target in several cancer types. Previous studies have shown that PRMT5 depletion leads to a reduction in FGFR3 and eIF4E expression. FGFR3 and eIF4E are oncogenes which play an important role in cellular proliferation and tumorigenesis. Furthermore, our group's previous research has demonstrated that PRMT5 inhibition shows significantly greater therapeutic effects in KRAS mutant CRC cells when compared to KRAS wild-type (WT) CRC cells.

Methodology

The Gene Expression Profiling Interactive Analysis (GEPIA) database was used to analyze the RNA-Seq data of CRC patients from The Cancer Genome Atlas (TCGA) database. We first used the GEPIA database to determine whether eIF4E and FGFR3 are overexpressed in colon and rectum patient tumor samples when compared to normal colon and rectum patient samples. We then used the GEPIA database to determine whether eIF4E and FGFR3 gene expression are correlated with PRMT5 and KRAS gene expression in colon and rectum patient tumor samples. We next used the STRING database to analyze whether eIF4E and FGFR3 interact with PRMT5 and KRAS. Finally, we used Biorender to develop a proposed molecular mechanism outlining how eIF4E and FGFR3 interact with PRMT5 and KRAS in CRC.

Results

• eIF4E is 2.4 and 2.2-Fold overexpressed in colon and rectum patient tumor samples, respectively, compared to normal colon and rectum patient samples (q < 0.01).

• FGFR3 is 2.3 and 3.7-Fold overexpressed in colon and rectum patient tumor samples, respectively, compared to normal colon and rectum patient samples (q < 0.01).

• eIF4E gene expression is positively correlated with PRMT5 (p < 0.01, R = 0.85) and KRAS (p < 0.01, R = 0.86) gene expression in colon and rectum patient tumor samples.

• FGFR3 gene expression is positively correlated with PRMT5 (p < 0.01, R = 0.61) and KRAS (p < 0.01, R = 0.63) gene expression in colon and rectum patient tumor samples.

• eIF4E and FGFR3 are shown to interact with PRMT5 and KRAS in the STRING database (Interaction score > 0.150).

• A molecular mechanism is proposed suggesting that PRMT5 inhibition may show greater therapeutic effects in KRAS mutant CRC, when compared to KRAS WT CRC, through PRMT5's interactions with eIF4E and FGFR3.

Conclusion

eIF4E and FGFR3 have been shown to be overexpressed and to interact with PRMT5 and KRAS in CRC. This significant observation can be therapeutically utilized towards developing new effective treatments for KRAS mutant CRC patients. Further analysis is currently in progress to verify the proposed molecular mechanism outlining how eIF4E and FGFR3 interact with PRMT5 and KRAS in CRC.

Citation Format: David Shifteh, Tzuriel Sapir, Moshe Pahmer, Sanjay Goel, Radhashree Maitra. FGFR3 and eIF4E are overexpressed and interact with PRMT5 and KRAS in CRC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 961.