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. Author manuscript; available in PMC: 2022 May 1.
Published in final edited form as: Gut. 2021 May 31;71(5):938–949. doi: 10.1136/gutjnl-2020-322835

Fig. 5. Correlation between CRC molecular subtypes and EpiCs can predict combinatorial treatments with high clinical significance.

Fig. 5.

A–C. Summary of IC50 values for 19 small molecule inhibitors (Y-axis) in cell lines with similar expression features to CMS1/EPIC1 (HCT116 or SW480) (A), CMS2/EPIC3 or EPIC4 (T84) (B), and CMS4/EPIC2 (SW620) (C). −Log(IC50) values are demonstrated on X-axis for each of the compounds. Drugs with higher −Log(IC50) are highlighted and were further used in combinatorial experiments.

D–F. Growth curves showing responses of CMS-specific CRC cell lines for the drug combinations identified based on the IC50 and AUC indices (panels A–C and Figures S8–S11): CMS1 lines with PARPi (olaparib) + BRDi (iBET-151) (D), CMS2 with EGFRi (gefitinib) + BRDi (RVX-208) (E), and CMS4 with TGFβi (SB431542) + BRDi (ISOX-DUAL) (F).

G–L. Tumor volume curves for xenografts in NUDE mice generated from transplantation of EpiC1/CMS1 (G-H), EpiC3–4/CMS2 (I-J), and EpiC2/CMS4 (K-L) cell lines upon treatment with inhibitors of EGFR (gefitinib, 100mg/kg), PARP (olaparib, 50mg/kg), TGF-β (SB431542, 10mg/kg), BRDi (i-BET151, 15mg/kg), or the combination of EGFRi + BRDi, the combination of PARPi + BRDi, and the combination of TGF-βi + BRDi along with the control vehicle group. Mice were treated every other day. Best treatment response was observed in the PARPi + BRDi combination in EpiC1/CMS1, EGFRi + BRDi combination in EpiC3–4/CMS2, and TGF-βi + BRDi combination in EpiC2/CMS4 lines. * shows p-values <0.05, and ** shows p-values <0.01.