Abstract 4858: Combined pan and precision targeting in extrachromosomal DNA-positive gastric cancer

Abstract Gastric adenocarcinoma (GAC) remains a major health challenge with high mortality due to late diagnosis, therapy resistance, and limited targeted options. Extrachromosomal DNA (ecDNA)—circular DNA elements carrying amplified oncogenes such as MYC, ERBB2, and EGFR—enhances transcriptional output, therapy resistance, and genomic instability. However, its role in GAC is poorly understood, and current models fail to recapitulate patient tumor complexity. Patient-derived organoids (PDOs) preserve tumor-specific features, including ecDNA, providing an ideal platform for mechanistic and therapeutic exploration.We hypothesize that ecDNA drives unique oncogenic programs in GAC that create exploitable vulnerabilities. Analysis of 221 TCGA-STAD samples with AmpliconArchitect identified ecDNA in 33.3% of primary tumors, absent in matched normal blood. ecDNA+ tumors showed distinct amplification patterns, with proteomic profiling revealing CHEK1 and TFRC enrichment, suggesting co-targetable vulnerabilities. To model these tumors, we established a PDO biobank comprising 5 primary and 9 ascites-derived PDOs. ecDNA was detected in 5/9 (55.6%) ascites-derived and 1/5 (20%) primary PDOs, consistent with ecDNA enrichment in metastatic settings. Amplified oncogenes included PTP4A3, for which inhibitors are available.RNA-seq comparison of ecDNA+ PDO 385 with ecDNA- PDOs (4666, 4601) revealed distinct transcriptional programs, with enriched expression on chromosomes 8 and 20. Transcription factor analysis identified MYC, also amplified as ecDNA. Immunofluorescence confirmed higher TFRC, CHEK1, MYC, and PRL3 (PTP4A3) expression and increased Ki67 in ecDNA+ PDO 385, supporting oncogene overexpression and aggressive growth. Drug screening predicted compounds reversing the ecDNA+ signature. Functional assays showed the TFRC inhibitor (TfR-1-IN-1) reduced proliferation of ecDNA+ PDO 385, while CHK1 inhibition had modest effects. Combined TFRC and CHK1 inhibition synergistically suppressed ecDNA+ PDO growth, with minimal effects on ecDNA- controls. These results highlight the selective vulnerability of ecDNA-driven tumors to co-targeting strategies. Using a PDO biobank, we aim to uncover and exploit vulnerabilities in ecDNA-positive GAC. Citation Format: Gengyi Zou, Melissa Pizzi, Aryanasingh Bhati, Bansi Vanparia, Wei-Chieh Yu, Ailing Scott, Yibo Fan, Calena Brown-Abel, Liyong Zeng, Johnson Amoah, Tanaya Alexander Washington, Yuan-Hung Lo, Vineet Bafna, Shilpa Dhar, Jaffer Ajani. Combined pan and precision targeting in extrachromosomal DNA-positive gastric cancer 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 4858.