Abstract A080: Systematic PDX-based drug screening reveals genotype-specific vulnerabilities and therapeutic combinatorial opportunities in colorectal cancer

Abstract Colorectal cancer (CRC) is characterized by extensive molecular heterogeneity, driven by oncogenic alterations such as KRAS, NRAS, and BRAF mutations. Although targeted therapies have shown promise, clinical efficacy remains variable and often limited by resistance, highlighting the need for improved molecular stratification and rational combination strategies. In this study, we employed a large-scale high-throughput in vivo drug screening using 140 patient-derived xenograft (PDX) models representing key CRC molecular subtypes: KRAS G12C (n=40), RAS/RAF wild-type (n=40), and BRAF V600E (n=60). Models were treated with standard-of-care (SOC) agents, including anti-EGFR, BRAF/EGFR, and KRAS G12C/EGFR inhibitors. Tumor growth inhibition was assessed alongside comprehensive molecular profiling via whole-exome sequencing, RNA sequencing, and Reverse Phase Protein Array (RPPA). Integrated multi-omics analyses identified biomarkers of drug response and mechanisms of resistance. Despite genomic diversity, resistant tumors frequently showed reactivation of MAPK signaling and RTK/PI3K–AKT pathway activation. BRAF V600E models exhibited heterogeneous responses to BRAF/EGFR inhibition (40% disease control rate), with improved efficacy upon co-targeting PI3K or downstream MAPK components. RAS/RAF wild-type models responded well to anti-EGFR therapy (40% disease control in previously treated models; 100% in treatment-naïve), although elevated RTK signaling conferred resistance, which was mitigated by downstream MAPK inhibition. KRAS G12C models showed modest responses to KRAS/EGFR inhibitors (70% disease control), with enhanced efficacy when combined with SOS1, SHP2, or AKT inhibitors. Genotype-specific vulnerabilities, such as WEE1 or EZH2 inhibitor sensitivity in KRAS G12C models, further support rational combination strategies. This large-scale PDX-based screen identifies actionable vulnerabilities across CRC genotypes and supports the development of genotype-informed combination therapies. These findings lay a strong preclinical foundation for guiding future precision oncology trials in colorectal cancer. Citation Format: Alexey Sorokin, Preeti Kanikarla, Jay Saynonh, Christian Y. Beke Onana, Fengqin Gao, Zhensheng Liu, Fangyang Wang, Christopher Bristow, Scott Kopetz. Systematic PDX-based drug screening reveals genotype-specific vulnerabilities and therapeutic combinatorial opportunities in colorectal cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A080.