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 - Funding Information:
This work was supported by grants to E.H.C. from the NIH (R01CA125562), Uniting Against Lung Cancer (GC2786) and Cycle for Survival (GC221279). This work was also supported by the NIH P30CA008748.
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 -