Abstract 1881: Drug combination screening of Ipatasertib and Abemaciclib with other targeted agents in complex multicellular tumor spheroids from the NCI-60 and the National Cancer Institute’s Patient-Derived Models Repository
Authors: Dexheimer Thomas Steven , Silvers Thomas , Delosh Rene , Laudeman Julie , Reinhart Russell , Ogle Chad , Paul Siddhartha , Coussens Nathan P. , Parchment Ralph E. , Morris Joel , Wright John , Takebe Naoko , Teicher Beverly A. , Doroshow James H. 
Published: June 2022

Abstract
Drug combinations are frequently used to improve clinical efficacy, to minimize toxicity, and to reduce the development of drug resistance. Here, we investigated the growth inhibitory activities of the pan-Akt inhibitor ipatasertib and the CDK4/6 inhibitor abemaciclib in combination with other targeted agents. Twelve well-characterized patient-derived cancer cell lines from the National Cancer Institute’s Patient-Derived Models Repository (https://pdmr.cancer.gov/models/database.htm) and seven established cell lines from the NCI-60 tumor cell line panel (https://dtp.cancer.gov/discovery_development/nci-60/cell_list.htm) were grown as multicellular 3D complex spheroids. The complex spheroids, a mixture of tumor cells (60%), endothelial cells (25%), and mesenchymal stem cells (15%), were grown for 3 days before drug(s) were added. All agents were tested both alone and in combinations at multiple concentrations up to their reported clinical Cmax value and cell viability was assayed using CellTiter-Glo 3D seven days after drug exposure. While abemaciclib had minimal activity as a single agent, ipatasertib was noticeably selective for tumor cells harboring activating PI3K/AKT/mTOR pathway variants. Dual inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways was one of the most effective combinations. For example, the combination of ipatasertib with the MEK inhibitor selumetinib or the ERK inhibitor ravoxertinib resulted in additive and/or synergistic cytotoxicity in over half the complex spheroid models screened. The V600E variant-specific BRAF inhibitor vemurafenib and the KRAS G12C selective inhibitor sotorasib in combination with ipatasertib showed activity in the one BRAF V600E and two KRAS G12C variant containing complex spheroid models, respectively. Another effective ipatasertib combination was vertical inhibition of the PI3K/AKT/mTOR pathway with the mTORC1/2 kinase inhibitor sapanisertib, which demonstrated additive and/or synergistic responses across multiple complex spheroid models. For abemaciclib, the most successful combination was with the CDK2/7/9 inhibitor BMS-387032, which achieved greater than one log of cytotoxicity in the majority of the complex spheroid models. For the combination of abemaciclib and selumetinib, there was a high correlation between the responses of two patient-derived cell lines grown as complex spheroids and their corresponding patient-derived xenografts (PDX). Additional PDX studies are planned for promising drug combinations from this in vitro screen. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.
Citation Format: Thomas Steven Dexheimer, Thomas Silvers, Rene Delosh, Julie Laudeman, Russell Reinhart, Chad Ogle, Siddhartha Paul, Nathan P. Coussens, Ralph E. Parchment, Joel Morris, John Wright, Naoko Takebe, Beverly A. Teicher, James H. Doroshow. Drug combination screening of Ipatasertib and Abemaciclib with other targeted agents in complex multicellular tumor spheroids from the NCI-60 and the National Cancer Institute’s Patient-Derived Models Repository [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 1881.