Abstract 6055: Targeting CEP55 as a universal oncogenic dependency: Integrating spatial multi-omics and targeted therapy across translational preclinical cancer models

Abstract CEP55 is an emerging oncogenic driver that is overexpressed across diverse cancers. It promotes genomic instability, and hyperactivates PI3K/AKT signaling, contributing to aggressive, metastatic, and therapy-resistant cancers. However, the mechanistic basis of CEP55-driven tumor progression and its potential as a therapeutic target have remained unresolved. To dissect Cep55 function across the evolutionary trajectory of transformation, we developed a hierarchical mouse embryonic fibroblast (MEF) cell lines encompassing primary (non-malignant), SV40-immortalised (early-transformation), and E1A/Ras-transformed (fully oncogenic) states with Cep55 deletion. This unbiased platform enabled stage-specific mapping of CEP55-controlled pathways. In parallel, we generated an inducible Cep55 KO mouse and interrogated CEP55 dependency in vivo using PTEN-deficient CreERT2 system and KRASLSL-G12D; TP53fl/fl (KP) lung adenocarcinoma GEMMs. We integrated quantitative proteomics, spatial transcriptomics, histopathology, and functional assays, with additional validation using human cancer datasets. Finally, to overcome the “undruggable” nature of CEP55, we deployed a CEP55-targeted antisense oligonucleotide encapsulated in tumor- antigen targeted lipid nanoparticles (ASO-LNP). Inducible Cep55 deletion was well tolerated in adult tissues, indicating Cep55 is non-essential for adult homeostasis but critical for tumorigenesis. Cep55 loss profoundly impaired oncogenic traits most strikingly in E1A/Ras MEFs, reducing proliferation, adhesion, migration, and invasion. In vivo, Cep55 ablation delayed tumor onset and progression, and significantly extended survival in both PTEN-deficient and KP GEMMs. Spatial transcriptomics revealed extensive CEP55-dependent remodeling of the tumor microenvironment, including disrupted extracellular matrix architecture, altered collagen networks, impaired integrin expression and trafficking, and collapse of focal-adhesion-PI3K/AKT-ERK signaling axes. Stress-response and anti-proliferative pathways were concomitantly activated. Proof-of-concept therapeutic studies showed that CEP55-targeting ASO-LNP suppressed tumor growth in vitro, providing a foundation for optimization and evaluation of CEP55 inhibition using precision RNA-based therapies in preclinical models. CEP55 is a fundamental oncogenic dependency that coordinates ECM remodeling, integrin signaling, and multiple oncogenic pathway activation during tumor initiation and progression. Its genetic ablation suppresses transformation, delays tumor growth, and prolongs survival across multiple cancer models. Together, these findings validate CEP55 as a compelling therapeutic target and establish ASO-LNP delivery as a promising strategy for targeting this previously undruggable node. Citation Format: Behnam Rashidieh, Pirjo Apaja, Quan Nguyen, Nigel McMillan, Kum Kum Khanna. Targeting CEP55 as a universal oncogenic dependency: Integrating spatial multi-omics and targeted therapy across translational preclinical cancer models [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 6055.