Figure 7

Drug combinations enhance killing of mutant RAS cells. (A) The combination of low (sub-lethal) doses of bortezomib and topotecan leads to a preferential loss of viability in HCT-116 as compared to HKE-3 cells. These effects can be seen across a wide topotecan titration range in combination with several bortezomib concentrations (left panel). Selected viability ratios are displayed (middle panel) and parallel differential apoptosis induction can also be monitored, indicated by apoptosis ratios (right panel). Data are represented as mean ± SD. (B) Different scheduling of drug treatment influences the effect of drug combinations: Adding bortezomib together with topotecan results in an elevated apoptosis induction in HCT-116 cells in comparison to HKE-3 cells as shown in A. The addition of bortezomib for 24 h prior to topotecan treatment does not elicit this response whereas addition of proteasome inhibitor 24 h post induction of DNA damage leads to an even greater differential effect. Apoptosis induction in the individual cell lines is displayed (left panel) and differential apoptosis induction is indicated by apoptosis ratios (right panel). Data are represented as mean ± SD. (C) Enhanced differential apoptosis induction effects can also be produced in response to scheduling the combination of gemcitabine and bortezomib. Selected apoptosis ratios are displayed. Data are represented as mean ± SD. (D) The application of low doses of bortezomib 24 h post induction of DNA damage can enhance the preferential loss of viability in KRAS mutant lung cancer cells as compared to KRAS wild-type cells. These effects can be seen across a wide doxorubicin titration range in combination with several bortezomib concentrations (curves representing the ratios of average values for each KRAS genotype, left panel; single data points representing individual cell lines, middle and right panels).