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. 2022 Feb 23;603(7899):166–173. doi: 10.1038/s41586-022-04437-2

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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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Extended Data Fig. 6 — a, b, 28 and 38 combinations are highly synergistic in KRAS mut (a) or MSS (b) colon cancer cell lines and some have ΔEmax or ΔIC50 biomarkers or are in clinical trials. Synergy rates of all colon combinations shown by KRAS mutant (mut; x-axis) versus wild-type (wt; y-axis;). b) or MSS (x-axis) versus MSI (y-axis; a). Colours represent biomarker or clinical trial presence. Vertical dashed line represents a synergy rate of 25% in MSS or KRAS mutant cell lines. n = 650 combinations. Pearson correlation with Fisher’s Z transform as statistical test. c, Loss of ERCC3 is associated with increased efficacy (ΔEmax) of linsitinib+MK-2206 in KRAS mutant colon (n = 20 wt; n = 5 loss). Median and interquartile range. p-value < 0.001, FDR < 0.05. d, Colon MSS cells show higher efficacy (ΔEmax) for AZD7762 (CHEK1/2) and camptothecin (TOP1). Drug combination responses were averaged across replicates and both anchor-library combination configurations were pooled (n = 31 MSS cell lines; n = 15 MSI cell lines). Median and interquartile range. Two-sided Welch’s t-test. e, AZD7762 and camptothecin have greater potency (ΔIC50) and efficacy (ΔEmax) in KRAS-TP53 double mutant colon cancer cells (n = 8 KRAS mutant & TP53 wild-type cell lines (wt); n = 16 KRAS-TP53 double mutant cell lines (mut)). Drug combination responses were averaged across replicates and both combination configurations were pooled. Median and interquartile range. Two-sided Welch’s t-test.