Abstract 3091: Patient-derived organoid drug responses corroborate known target-drug interactions for selected anticancer agents
Authors: Hose Curtis , Harris Erik , Connelly John , Campbell Petreena S. , Ortiz Mariaestela , Jones Eric , Newton Dianne , Evrard Yvonne A. , Hollingshead Melinda , Parchment Ralph , Teicher Beverly A. , Coussens Nathan P. , Doroshow James H. , Rapisarda Annamaria 
Published: June 2022

Abstract
Patient-derived organoids (PDOrgs) are heterogeneous three-dimensional cellular clusters that have been shown to recapitulate the tumor histology and genetic alterations of their originating tissue. Numerous studies suggest the in vitro drug responses of tumor organoids align with in vivo responses. In this study, we evaluated fourteen anticancer agents against a cohort of PDOrgs from three disease histologies: colon, pancreatic, and non-small cell lung adenocarcinoma. The PDOrgs were obtained from the National Cancer Institute’s Patient-Derived Models Repository (https://pdmr.cancer.gov): a resource that offers clinically annotated and molecularly characterized models. The PDOrg models were selected for specific genetic variants of KRAS and BRAF, or different RNA levels of ABCB1, an ATP-dependent efflux pump. The approved and investigational agents were selected to target specific genetic variants and pathways: KRAS G12C covalent inhibitors (sotorasib and MRTX-1257), RAS pathway inhibitors (BAY-293, BI-3406 and TNO-155), BRAF V600E/K inhibitors (dabrafenib and encorafenib), ABCB1 substrates (paclitaxel, doxorubicin, 5-FU, AZD-1775, and SN-38), and ABCB1 non-substrates (gemcitabine and trametinib). The goal of the study was to assess whether the sensitivities of PDOrgs to therapeutic agents matched these genetic profiles under standard in vitro conditions. PDOrgs were seeded into 384-well microplates, in a semi-automated fashion, and exposed to nine concentrations of each anticancer agent for six days followed by cell viability assessment by CellTiter-Glo 3D. Data analysis was performed using GRmetrics, an R package for calculation and visualization of concentration-response metrics based on growth rate inhibition (https://git.bioconductor.org/packages/GRmetrics). These data demonstrated that PDOrgs harboring a KRAS G12C variant were uniquely sensitive to sotorasib and MRTX-1257 and were, overall, more sensitive to the other RAS pathway targeting agents. Conversely, PDOrgs harboring wild type RAS and other KRAS variants were largely unresponsive to these targeted agents. Likewise, only PDOrgs harboring the BRAF V600E variant were sensitive to dabrafenib and encorafenib. For the majority of PDOrgs, the pharmacological responses to agents that are ABCB1 substrates inversely correlated with ABCB1 RNA expression. This study demonstrates the ability of organoids to serve as useful models for evaluating therapeutic responses to anticancer agents, including identifying known target-drug associations. Moreover, the technical conditions, as well as the selected PDOrgs and therapeutic agents, may be used as a reference set for the validation of a fully automated PDOrg screening system. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.
Citation Format: Curtis Hose, Erik Harris, John Connelly, Petreena S. Campbell, Mariaestela Ortiz, Eric Jones, Dianne Newton, Yvonne A. Evrard, Melinda Hollingshead, Ralph Parchment, Beverly A. Teicher, Nathan P. Coussens, James H. Doroshow, Annamaria Rapisarda. Patient-derived organoid drug responses corroborate known target-drug interactions for selected anticancer agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3091.