Clinical relevance and combinatorial treatment for CHOP-resistant DLBCL. (A) Kaplan-Meier survival curves based on KLHL6 expression (top 20% vs bottom 20%) data for DLBCL tumors with partial response to R-CHOP (GSE31312) is shown. The P value from log-rank (Mantel-Cox) test is shown (n = 11 per group). (B) Kaplan-Meier survival analysis of DLBCL patients harboring NOTCH2 (WT) or mutations abolishing the FBXW7-degron alone (NOTCH2 [ΔdegFBXW7]) or the KLHL6-degron and FBXW7-degron (NOTCH2 [ΔdegKLHL6/ΔdegFBXW7]) (NOTCH2 [WT], n = 896; NOTCH2 [ΔdegFBXW7], n = 16; NOTCH2 [ΔdegKLHL6/ΔdegFBXW7]; n = 5; Mantel-Cox test).²⁴ (C) 1 × 10⁷ U2932 cells were xenografted in the flanks of NSG mice. After the average tumor volumes reached 100 mm³, mice were treated with cyclophosphamide (30 mg/kg), doxorubicin (2.48 mg/kg), and vincristine (0.38 mg/kg) IV on day 1 and prednisone (0.2 mg/kg) was given via oral gavage daily with ipataserbib (50 mg/kg) or nirogacestat (100 mg/kg), for 5 days and 7 days respectively, or combination. The experimental end point was reached when the tumor volume reached 1000 mm³. Each line represents one tumor in one mouse (n = 5 per group, two-way ANOVA). (D) Kaplan-Meier survival analysis of mice shown in (C), (n = 5 per group, the Mantel-Cox test). (E) Same as that in panel C, but U2932 cells stably expressing the indicated NOTCH2 cDNA were xenografted. (F) Kaplan-Meier survival analysis of mice shown in panel E (n = 5 per group; the Mantel-Cox test).