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. Author manuscript; available in PMC: 2022 Apr 12.
Published in final edited form as: Cancer Cell. 2021 Apr 12;39(4):566–579.e7. doi: 10.1016/j.ccell.2021.02.014

Figure 1: In vitro drug response profiles of SCLC reveal DNA damage response-related vulnerabilities.

Figure 1:

A) Heatmap of ranked drug activities for seven SCLC cell lines (DMS114, DMS79, H187, H196, H446, H524 and H889) screened using the MIPE 5.0 library of approved and investigational drugs (n=2480). Activity scores based on Z-transformed area under the curve values. Mechanistic classes enriched among highly active agents are shown on the right panel. B) Drug-target enrichment analysis plots highlighting synergy of TOP1 inhibitors with CHK1 and ATR inhibitors. TOP1-inhibitor combinations examined in combination with MIPE 5.0 library using indotecan (LMP400), a next-generation clinical TOP1 inhibitor. TOP1 inhibitor-drug pairs ranked using the ExcessHSA metric. C) Unsupervised hierarchical clustering based on the correlation of the ExcessHSA showing drug-clusters with similar combination profiles. In this screen, 44 drugs selected based on single-drug activities, synergies from indotecan-combinations, and mechanistic interest were tested in combination (n=946 combinations). D) Correlation heatmap of the 44-drug all-versus-all combination screen highlighting synergistic clusters. 10 × 10 % response and ΔBliss heat maps for the combination of E) topotecan and M6620, and F) indotecan and M6620 across defined concentration ranges in H446 SCLC cell line. SCLC: small cell lung cancer; TOP1: topoisomerase 1; ExcessHSA: Excess over the Highest Single Agent. See also Table S1 and Fig. S1.