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. 2023 Jun 23;14:3762. doi: 10.1038/s41467-023-39374-9

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© This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Dose-response curve of PEV derived from MIPE 5.0 library screen in HCT116 CRC cells. b Scheme of 6 × 6 matrix screening to examine PEV in combination with the MIPE5.0 library in HCT116 cells. In response matric, red indicates strong response whereas black indicates poor response. In excess over the Highest Single Agent (ExcessHSA or ΔHSA) metric, orange indicates synergy whereas blue indicates resistance. c Drug-target enrichment analysis plots highlighting the synergy of PEV with TOP1 inhibitors. PEV-TOP1 inhibitor pairs ranked using the ExcessHSA metric. d Response (top panels) and ΔHSA (bottom panels) heatmaps for the combination of PEV with camptothecins irinotecan and SN38 (the bioactive metabolite of irinotecan) and indenoisoquinolines LMP776 (indimitecan) and LM744 across defined concentration ranges in HCT116 cells. e Top panels: viability curves for 72 h treatments with SN38 at defined concentrations in the indicated CRC cell lines (mean ± SD, N = 3 biologically independent experiments) using ATPlite Luminescence Assay. Cells were treated with PEV at defined concentrations 4 h before SN38. Bottom panels: SN38-PEV pairs ranked by ExcessHSA metric using Combenefit, an interactive platform for the analysis of drug combinations.