Abstract 1674: Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal organoids

Abstract Thirty-two patient-derived colorectal organoid models were selected from the NCI’s Patient-Derived Models Repository (https://pdmr.cancer.gov) to serve in a high-throughput screening panel. The models were derived from primary or metastatic tumors of patients with varied ancestries, ranging in age from 32–90 yrs, that were either previously treated or treatment naïve. Variations were determined in microsatellite stability, consensus molecular subtype, and genetics, including clinically relevant oncogenic variants of RAS, BRAF and PIK3CA. A screen was conducted with twenty-two combinations of agents, including SOC and investigational oncology drugs. Organoids were exposed to single agents or combinations at four concentrations covering 2 logs up to the clinical Cmax, if known. Following compound addition, organoid growth was measured by live bright field imaging every 24 h and cell viability was determined by CellTiter-Glo 3D at 48 h and 168 h. Modest responses were observed in most models from the combination of leucovorin with 5-FU; however, >1 log of cytotoxicity was observed in only several models. The panel was more responsive to FOLFOX, which was consistent with the sensitivity of models to oxaliplatin. Responses to TAS-102 varied and >1 log of cytotoxicity was observed in several models. The MEK inhibitor cobimetinib was active in models with wild type KRAS and generally more active in models with oncogenic KRAS. Combination of the BCL-2/BCL-xL inhibitor pelcitoclax plus cobimetinib achieved >1 log of cytotoxicity in most organoid models. Combinations of cobimetinib with the EGFR inhibitors erlotinib, afatinib or cetuximab demonstrated synergy in many organoids according to the Bliss independence model and frequently achieved ≥1 log of cytotoxicity. As a single agent, the KRAS G12D inhibitor MRTX1133 was active against organoid models harboring KRAS G12D. The combination of cobimetinib and MRTX1133 had synergistic activity by Bliss independence in multiple organoid models and frequently achieved >1 log of cytotoxicity. Additionally, combinations of MRTX1133 with an EGFR inhibitor had additive and greater-than-additive cytotoxicity in a range of organoids. The pan-RAS(ON) inhibitor RMC-6236 had substantial single-agent activity against organoid models with wild type KRAS and most models with an oncogenic KRAS variant. In combination with cobimetinib, RMC-6236 demonstrated additive and synergistic cytotoxicity, frequently ≥1 log, in organoid models with BRAF V600E and harboring wild type KRAS or an oncogenic variant. When combined with the pan-PI3K inhibitor copanlisib, RMC-6236 demonstrated substantial synergy, achieving ≥2 logs of cytotoxicity in several organoid models with wild type KRAS. Complimentary PDX studies are in progress. Funded by NCI Contract No. 75N91019D00024 & 75N91020F00032. Citation Format: Nathan P. Coussens, Thomas S. Dexheimer, Phillip R. Sanchez, Thomas Silvers, Eric M. Jones, Bryce M. Butler, John R. Britt, Carmen Allegra, James H. Doroshow, Beverly A. Teicher. Combinatorial screen with standard of care and selected anticancer agents identifies multiple combinations with activity against a panel of patient-derived colorectal 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 1674.