Abstract 5026: Discovery of oncogenic mediator genes in rectal cancer chemotherapy response using gene expression data from matched tumor and patient-derived organoids

Abstract Rectal cancer (RC) remains a significant clinical challenge, in part due to chemotherapy resistance encountered in neoadjuvant treatment approaches. To address this, we utilized a unique platform integrating gene expression data from RC tumor tissues and matched patient-derived organoids (PDO). Gene expression data were analyzed using the computational tool Moonlight to investigate the molecular mechanisms underlying chemotherapy response. We hypothesized that combining genomic data from RC PDOs and matched tumors would implicate molecular targets predicting chemotherapy response and clinical outcomes better than targets identified using RC tumor tissue or RC PDO input alone. We analyzed 18 tissue samples and 32 matched PDOs, capturing a comprehensive representation of tumor biology. Our integrative approach involved differential expression analyses (DEAs) and gene regulatory network (GRN) studies, identifying 5,199 genes regulating at least one potential regulon. Focusing on cancer-associated biological processes curated in Moonlight, we highlighted 2,118 regulator-regulon pairs with potential roles in oncogenic processes. Further integration with DEA results revealed 334 regulator-regulon pairs significantly enriched in both tissue and PDO samples, designating these regulators as oncogenic mediators (OMs). Among them, five genes—BTK, CDK1, LAX1, NAT2, and RAD51AP1—were associated with FOLFOX response. Survival analysis across four independent cohorts further validated CDK1, LAX1, NAT2, and RAD51AP1 as indicators of prolonged recurrence-free survival (RFS), demonstrating consistent patterns associated with good prognosis. These findings provide new insights into the molecular mechanisms of chemotherapy response in RC, and validation of these targets is ongoing. Our integrated approach underscores the translational relevance of PDOs and demonstrates the utility of Moonlight in identifying potential therapeutic targets, setting a new benchmark for precision medicine in rectal cancer. Citation Format: Hanchen Huang, Wini Zambare, Chao Wu, Antonio Colaprico, Janet Alvarez, Min Jung Kim, Aron Bercz, Paulina Bleu, Lily Wang, Philip B. Paty, Paul B. Romesser, J. Joshua Smith, X. Steven Chen. Discovery of oncogenic mediator genes in rectal cancer chemotherapy response using gene expression data from matched tumor and patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5026.