Abstract C045: Combinations of PI3K inhibitors with targeted oncology agents in multicellular spheroid models
Authors: Dexheimer Thomas S , Silvers Thomas , Coussens Nathan P , Said Rabih , Teicher Beverly A , Doroshow James H 
Published: December 2023

Abstract
Dysregulation of the phosphatidylinositol 3-kinase (PI3K) pathway plays a significant role in cancer, and inhibitors offer a promising strategy for targeted therapies. The selectivity of current inhibitors varies against different PI3K isoforms or subtypes. For example, alpelisib and inavolisib predominantly target the α-isoform, whereas duvelisib targets the δ- and γ-isoforms. By contrast, copanlisib is a pan-PI3K inhibitor, exhibiting activity against all isoforms. In combinations with other targeted agents, we investigated the activity of these four PI3K inhibitors against multicellular spheroids. The multicellular spheroids, grown from 60% malignant cells, 25% endothelial cells, and 15% mesenchymal stem cells, served as a model for human solid tumors that incorporates both malignant and stromal components. Thirty multicellular spheroid models were grown from various malignant cell types, including twenty-seven patient-derived cancer cell lines obtained from the NCI Patient-Derived Models Repository (https://pdmr.cancer.gov/) and three established cell lines from the NCI-60 human tumor cell line panel. After three days of spheroid growth, anticancer agents were introduced at concentrations up to their reported clinical Cmax value, if known. After seven days of drug exposure, cell viability was measured using the CellTiter-Glo 3D assay. Among the various drug combinations evaluated, simultaneous targeting of the PI3K and RAS pathways was highly effective, particularly against malignant cell lines with an activated RAS pathway. Notably, additive and/or synergistic activities were observed when either the α-isoform-specific PI3K inhibitors (alpelisib and inavolisib) or the pan-PI3K inhibitor (copanlisib) was combined with either the MEK inhibitor selumetinib, the ERK inhibitor ravoxertinib, or the type II pan-RAF kinase inhibitor DAY101. Additionally, combinations of the same three PI3K inhibitors with variant-specific inhibitors, such as vemurafenib (BRAF V600E), sotorasib (KRAS G12C), or MTRX-1133 (KRAS G12D) demonstrated selective activity against cell lines carrying the variant. Another effective combination with PI3K inhibitors was achieved with vertical inhibition of the PI3K pathway through the addition of the mTORC1/2 kinase inhibitor sapanisertib. Finally, combinations of a CDK4/6 inhibitor (abemaciclib or palbociclib) with a PI3K inhibitor demonstrated synergistic activities, although they were not as potent as other combinations. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261201500003I.
Citation Format: Thomas S Dexheimer, Thomas Silvers, Nathan P Coussens, Rabih Said, Beverly A Teicher, James H Doroshow. Combinations of PI3K inhibitors with targeted oncology agents in multicellular spheroid models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C045.