Here, using unbiased pooled short hairpin RNA (shRNA) screening, drug sensitivity profiling in a large cancer cell line panel, and whole-transcriptome sequencing (RNA-seq), we reveal that the differential sensitivity to splicing modulation of BH domain containing antiapoptotic BCL2 family genes provides mechanism-based therapeutic strategies for SF3b-targeting small molecule splicing modulator. The gene discussed is BCL2; the disease is cancer.