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. 2022 Apr 20;604(7907):749–756. doi: 10.1038/s41586-022-04638-9

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© The Author(s) 2022

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. 4 — a, RP-6306 resistance screen for dose required to kill 80% of cells (LD₈₀) performed in FT282-hTERT TP53^R175H CCNE1 (C3 and C4) with DrugZ scores for C3 plotted. Genes with DrugZ > 9 in both C3 and C4 screens (blue) and FOXM1 (red) are shown for reference. b, Gene set enrichment analysis (GSEA) of differential gene expression in FT282 parental (WT) versus CCNE1-high (C3) cells for genes co-regulated by MMB–FOXM1. c, EC₅₀ values for RP-6306 in CCNE1-high FT282-hTERT TP53^R175H cells nucleofected with Cas9 ribonucleoproteins assembled with the indicated sgRNAs. Growth was monitored by clonogenic survival assay. d, QIBC analysis of cyclin B cytoplasmic intensity, EdU incorporation and DNA content (measured with DAPI). Representative QIBC plots (left) and cytoplasmic cyclin B intensity (right) quantification in late S or G2/M. P values determined by two-tailed t-test. e, Clonogenic survival of FT282-hTERT TP53^R175H CCNB1-2A-GFP and wild-type parental cells treated with RP-6306. Quantification (left) and representative images of plates stained with crystal violet (right). f, Growth inhibition relative to DMSO control of parental (WT) and CCNE1-high FT282-hTERT TP53^R175H cells and HCC1569 cells after the indicated treatments. Growth was monitored with an Incucyte live-cell imager for up to six population doublings. g, QIBC quantification of cells with pan-γH2AX in response to the indicated RP-6306–gemcitabine combinations. Data in c–g are mean ± s.d. (n = 3).

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