Abstract A001: Uncovering the role of IMP2 in RAS signaling and colorectal cancer progression

Abstract Colorectal cancer remains challenging to treat, in part because of the difficulty of achieving sustained inhibition of mutant isoforms of KRAS signaling. The frequent emergence of therapeutic resistance via restored or compensatory signaling is often driven by wild-type (WT) RAS proteins. Since KRAS WT can rapidly reactivate MAPK and PI3K cascades even when mutant KRAS is suppressed, defining how KRAS WT is regulated is essential to overcoming the signaling rebound that undermines current therapeutic strategies. This prompts the need to understand how RAS signaling, both mutant and wild type, is regulated at the mRNA level. RNA-binding proteins (RBPs) play a crucial role in post-transcriptional gene regulation, influencing mRNA transport, localization, splicing, translation, and stability. Insulin Like Growth Factor 2 mRNA Binding Protein 2 (IMP2) is an N6-methyladenosine (m6A) reader that is significantly overexpressed in colorectal cancer (CRC) and is associated with poor prognosis. Because restored KRAS WT signaling represents a major mechanism of resistance in CRC, defining how IMP2 influences KRAS mRNA levels and downstream effectors has the potential to clarify how both mutant and wild-type KRAS pools are maintained during therapy. The interplay between IMP2 and KRAS has not been previously characterized, making this a critical area of investigation. We modulated IMP2 using RNAi knockdown, cDNA overexpression, and pharmacological inhibitors of its functional activity to determine the effects on KRAS-driven cellular behaviors and investigate the broader role of IMP2 in CRC. Using eCLIP-seq to determine IMP2-bound mRNAs, we identified novel IMP2 binding sites on the 5’UTR of KRAS mRNA. We performed GLORI-seq to identify transcriptomic m6A sites in CRC cells. Knockdown and pharmacological inhibition of IMP2 decreased the expression of KRAS mRNA and protein, and altered multiple components of RAS signaling including downstream effectors such as p-ERK, p-AKT P-4EBP1, and stimulated feedback responses in upstream regulators such as MIG6 and EGFR. Together, this indicates that IMP2 may serve as a central modulator of pathway activity and suggest that IMP2 may act as a direct positive regulator of KRAS mRNA. By elucidating the functions of IMP2 in oncogenic signaling, this research indicates IMP2 as a potential therapeutic target for CRC. Citation Format: Jessica Das, Khizr Khan, Ottavia Busia-Bourdain, Andrew Lerner. Wolfe. Uncovering the role of IMP2 in RAS signaling and colorectal cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: RAS Oncogenesis and Therapeutics; 2026 Mar 5-8; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_1):Abstract nr A001.