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

Akane Inoue-Yamauchi; Paul S. Jeng; Kwanghee Kim; Hui Chen Chen; Song Han; Yogesh Tengarai Ganesan; Kota Ishizawa; Sylvia Jebiwott; Yiyu Dong; Maria C. Pietanza; Matthew D. Hellmann; Mark G. Kris; James J. Hsieh; Emily H. Cheng

doi:10.1038/ncomms16078

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

Akane Inoue-Yamauchi
, Paul S. Jeng
, Kwanghee Kim
, Hui Chen Chen
, Song Han
, Yogesh Tengarai Ganesan
, Kota Ishizawa
, Sylvia Jebiwott
, Yiyu Dong
, Maria C. Pietanza
, Matthew D. Hellmann
, Mark G. Kris
, James J. Hsieh
, Emily H. Cheng

Research output: Contribution to journal › Article › peer-review

158 Scopus citations

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 with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-X_L, 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.

Original language	English
Article number	16078
Journal	Nature communications
Volume	8
DOIs	https://doi.org/10.1038/ncomms16078
State	Published - Jul 17 2017

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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.",

author = "Akane Inoue-Yamauchi and Jeng, \{Paul S.\} and Kwanghee Kim and Chen, \{Hui Chen\} and Song Han and Ganesan, \{Yogesh Tengarai\} and Kota Ishizawa and Sylvia Jebiwott and Yiyu Dong and Pietanza, \{Maria C.\} and Hellmann, \{Matthew D.\} and Kris, \{Mark G.\} and Hsieh, \{James J.\} and Cheng, \{Emily H.\}",

note = "Publisher Copyright: {\textcopyright} 2017 The Author(s).",

year = "2017",

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doi = "10.1038/ncomms16078",

language = "English",

volume = "8",

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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.

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 - https://www.scopus.com/pages/publications/85024492846

U2 - 10.1038/ncomms16078

DO - 10.1038/ncomms16078

M3 - Article

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SN - 2041-1723

VL - 8

JO - Nature communications

JF - Nature communications

M1 - 16078

ER -

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

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