Fig. 6.

Effects of AZD6738 monotherapy or combined with CDC7 inhibitor in vivo. a Tumor volumes of Huh7 and MHCC97H tumor xenografts in BALB/c nude mice following vehicle or AZD6738 (50 mg/kg) treatment for 12 days (Huh7 xenograft) and 18 days (MHCC97H xenograft), respectively. b γH2AX staining was performed on formalin-fixed paraffin-embedded Huh7 and MHCC97H xenografts after 12 days (Huh7 xenograft) and 18 days (MHCC97H xenograft) of treatment with vehicle or AZD6738. c Tumor volumes of PLC/PRF/5 tumor xenografts in BALB/c nude mice following vehicle, AZD6738 (50 mg/kg), XL413 (50 mg/kg) or combination treatment for 12 days. d γH2AX staining was performed on formalin-fixed paraffin-embedded PLC/PRF/5 xenografts after 12 days treatment with vehicle, AZD6738, XL413 or combination. e Potential classification and treatment strategies for HCC patients. Upregulation of genes implicated in response to replication stress could serve as a biomarker for the classification of HCC patients. The heatmap shows expression level of genes implicated in replication stress of tumor and adjacent tissues. Among 159 patients with both tumor and paired adjacent tissues available, 69 patients have HCC tissues showing high replication stress, while the remaining 90 patients have HCC tissues with low replication stress according to K-means clustering. Kaplan-Meier curves depicting that high replication stress in tumor tissues correlates with poor prognosis of the patients. Patients with HCC tumors showing high replication stress would potentially benefit from ATR or CHK1 inhibition only, whereas patients with tumors that show low replication stress would need CDC7 inhibition to induce replication stress and sensitize tumor cells to ATR or CHK1 inhibition. *P < 0.05, **P < 0.01 and ***P < 0.001A