Figure 3 from Bcl-xL Is a Key Mediator of Apoptosis Following KRASG12C Inhibition in KRASG12C-mutant Colorectal Cancer

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Bcl-xL regulates intrinsic resistance to KRASG12C inhibition in KRASG12C MT colorectal cancer. A, Targeted siRNA screen in SW837 and SNU1411 cells. Top: SW837 and SNU1411 cells were reverse transfected with 10 nmol/L ON-Targetplus siRNA's targeting 42 genes in the absence or presence of 1 μmol/L AZ’1569 for 72 hours and cell viability was evaluated using the CTG assay. Scatter plot showing rZ for siRNA screen in SW837 and SNU1411 cells. Positive scores indicate potential mediators of sensitivity to AZ’1569, while negative scores indicate mediators of resistance to AZ’1569. Dashed lines indicate rZ = 0, 1.5, and −1.5; cut-off thresholds of ±1.5 were applied to the data. Bottom: The siRNA approach and analysis. XY graph illustrates hits resulting in sensitization or resistance to AZ’1569 in both cell lines. Data show average rZ-scores from three independent experiments. B, Colorectal cancer cells were transfected with 10 nmol/L on-target SMARTpool siRNA against BCL2L1 and cotreated with 1 μmol/L AZ’1569 (0.25 μmol/L AZ’1569 for RW7213 and C106 cells) for 24 hours (48 hours for SNU1411) and apoptosis assessed by WB for PARP and cleaved caspase 8 and 3 (top) and caspase 3/7 activity assay (bottom). n.d denotes not detected. A two-way ANOVA was used to evaluate significance. C, Expression of PARP, cleaved caspase 9, caspase 8, Myc-tag, and KRAS in SW837 and RW7213 cells transiently transfected with 1 μg of Myc-tagged Bcl-xL for 24 hours, followed by treatment with 1 μmol/L AZ’1569 (AZD) for the indicated times. Caspase-3/7 activity on cell lysates was also determined. A two-way ANOVA was used to evaluate significance.

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