Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy.

ABSTRACT: BCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-X_L or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-X_L inhibitor, prevented BCL-X_L from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-X_L-addicted cells with low activator BH3s and BCL-X_L overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized wi

SUBMITTER: Inoue-Yamauchi A 

PROVIDER: S-EPMC5520052 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature