TY - JOUR
T1 - Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy
AU - Inoue-Yamauchi, Akane
AU - Jeng, Paul S.
AU - Kim, Kwanghee
AU - Chen, Hui Chen
AU - Han, Song
AU - Ganesan, Yogesh Tengarai
AU - Ishizawa, Kota
AU - Jebiwott, Sylvia
AU - Dong, Yiyu
AU - Pietanza, Maria C.
AU - Hellmann, Matthew D.
AU - Kris, Mark G.
AU - Hsieh, James J.
AU - Cheng, Emily H.
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/7/17
Y1 - 2017/7/17
N2 - 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-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.
AB - 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-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.
UR - http://www.scopus.com/inward/record.url?scp=85024492846&partnerID=8YFLogxK
U2 - 10.1038/ncomms16078
DO - 10.1038/ncomms16078
M3 - Article
C2 - 28714472
AN - SCOPUS:85024492846
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 16078
ER -