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

Authors: Inoue-Yamauchi, A.; Jeng, P. S.; Kim, K.; Chen, H. C.; Han, S.; Ganesan, Y. T.; Ishizawa, K.; Jebiwott, S.; Dong, Y.; Pietanza, M. C.; Hellmann, M. D.; Kris, M. G.; Hsieh, J. J.; Cheng, E. H.
Article Title: 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-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. © 2017 The Author(s).
Journal Title: Nature Communications
Volume: 8
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2017-07-17
Start Page: 16078
Language: English
DOI: 10.1038/ncomms16078
PROVIDER: scopus
PMCID: PMC5520052
PUBMED: 28714472
Notes: Article -- Export Date: 2 August 2017 -- Source: Scopus
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MSK Authors
  1. Maria C Pietanza
    115 Pietanza
  2. Yiyu Dong
    16 Dong
  3. Emily H Cheng
    55 Cheng
  4. Mark Kris
    605 Kris
  5. Matthew David Hellmann
    168 Hellmann
  6. Paul S Jeng
    3 Jeng
  7. Kwanghee   Kim
    10 Kim
  8. Hui-Chen   Chen
    6 Chen
  9. Song   Han
    5 Han