Abstract 6335: Temporal profiling of the EGF-induced transcriptional cascade in PC3 prostate cancer cells reveals biphasic oncogenic reprogramming

Abstract The Epidermal Growth Factor (EGF) signaling pathway is a potent driver of prostate cancer progression, yet a comprehensive, time-resolved understanding of its transcriptional dynamics remains incomplete. This study employed temporal RNA-sequencing on PC3 prostate cancer cells to profile the transcriptomic landscape at critical intervals (0, 30 min, 1 h, 6 h) following EGF stimulation. Our analysis reveals a biphasic oncogenic reprogramming. The initial phase, evident within 30-60 minutes, is characterized by a rapid surge of immediate-early genes (FOS, JUN, EGR family) and the coordinated activation of pathways promoting cell migration, inflammation (NF-κB, IL-17), and early signaling (MAPK). This is followed by a distinct secondary phase at 6 hours, where the transcriptome pivots to strongly enrich processes dedicated to sustained growth and survival, including cell cycle progression, DNA replication, and the PI3K-AKT-mTOR signaling axis. Having established this kinetic map, we demonstrate that the previously characterized L-peptide inhibitor, LA3IK, effectively suppresses this program. Co-treatment with EGF and LA3IK for 6 hours resulted in significant inhibition of genes across these critical pathways, including PI3K-AKT, MAPK, and cell cycle. To overcome the proteolytic limitations of the L-peptide, we then employed its D-enantiomer, D-LA3IK, which yielded superior results, driving a more profound and comprehensive reversal of the EGF-induced transcriptome and exhibiting enhanced efficacy in functional assays. This work delineates the phased transcriptional cascade orchestrated by EGF and establishes targeted peptide inhibition, particularly with the stable D-isomer, as a potent strategy to disrupt this oncogenic program. Citation Format: Amit Kumar Tripathi, Jamboor K. Vishwanatha. Temporal profiling of the EGF-induced transcriptional cascade in PC3 prostate cancer cells reveals biphasic oncogenic reprogramming [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6335.