Fig. 6: MYC or EGFR overexpression is sufficient to confer DDA cytotoxicity.

a Kaplan–Meier plot showing that patients with tumors overexpressing both EGFR and MYC are associated with a significantly worse survival than are patients with tumors expressing low levels of both EGFR and MYC. Patients ranked based on the expression of EGFR and MYC were classified into four groups, named “low EGFR low MYC (N = 359)”, “low EGFR high MYC (N = 220)”, “high EGFR low MYC (N = 225)”, and “high EGFR high MYC (N = 372)”. Overall survival (OS) was compared among these groups. The F test was used to compare the variance between groups (P > 0.05, ns; *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001). b Micrographs showing the morphology of the indicated MCF10A stable cell lines after 24 h of treatment with 5 µM tcyDTDO, 12.5 ng/ml TRAIL, tcyDTDO + TRAIL, tcyDTDO + TRAIL + 10 µM Q-VD-OPH, or 10 µM Lapatinib. c Immunoblot analysis of stable MCF10A cell lines treated for 24 h as in b. d Model for how DDAs activate TRAIL/DR5-induced cell death in an oncogene-dependent manner. In the context of EGFR or HER2 overexpression, DDAs elevate ER stress resulting in transcriptional upregulation of DR5. Through a second mechanism, DDAs alter DR5 disulfide bonding to promote DR5 protein stabilization, oligomerization, and activation of pro-apoptotic signaling. Cytotoxicity of DDAs and TRAIL is also potentiated in MYC-overexpressing cells.