Figure 4 from Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer

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High-throughput drug screen reveals that pharmacologic inhibition of Bcl-xL synergizes with KRASG12C inhibition in KRASG12C MT colorectal cancer. A, SW837 and SNU1411 cells were cotreated with 1 μmol/L AZ’1569 alone or combined with a panel of 45 small-molecule inhibitors for 72 hours and cell viability assessed using the CTG assay. Three concentrations per drug were tested (Supplementary Table S2). Cell viability was analyzed using a CTG assay. Scatter plot showing rZ for each compound concentration used in the drug screen. Negative rZ-scores indicate agents that sensitize to AZ’1569, and vice versa. Dashed lines on graphs indicate values of 1.5 and −1.5. Venn diagram indicates number of compounds (past a threshold of rZ = −1.5) that resulted in sensitization to AZ’1569 in both cell lines. B, CTG cell viability assays in KRASG12C MT colorectal cancer cells cotreated with AZ’1569 and ABT-737 for 72 hours. CI values were calculated to evaluate the nature of interaction. Absolute cell viability for AZ’1569/ABT-737 combinations in SW847 and SNU1411 cell lines are also shown. Dashed lines on graphs represent 50% cell viability. C, PARP, cleaved C9, cleaved C8, cleaved C3, and KRAS expression levels in KRASG12C MT colorectal cancer cells cotreated with AZ’1569 and ABT-737 for 48 hours (24 hours for RW7213, SW1463, and V481 cells). CM = combination. D,KRASG12C MT colorectal cancer cells were treated with AZ’1569 alone or combined with cetuximab or ABT-737 (0.25 μmol/L for C106, LIM2099, SNU1411; 0.5 μmol/L for SW837, V481, RW7213 and 2.5 μmol/L for SW1463) for 48 hours (24 hours for C106 cells) and PARP, cleaved C9, cleaved C8, and cleaved C3 determined by WB.

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