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

Akane Inoue-Yamauchi1, Paul S Jeng1, Kwanghee Kim2

  • 1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.

Nature Communications
|July 18, 2017
PubMed

Insights

Targeting BCL-2 family proteins is key for cancer therapy. This study reveals how small cell lung cancer cells depend on specific proteins, guiding new combination therapies for better treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • BCL-2 family proteins regulate mitochondrial apoptosis and are crucial anti-cancer targets.
  • Cancer cells exhibit differential dependence on anti-apoptotic proteins like BCL-2, BCL-XL, and MCL-1.

Purpose of the Study:

  • To investigate the differential addiction of small cell lung cancer (SCLC) cells to BCL-2 family proteins.
  • To identify novel therapeutic strategies by combining BCL-2/BCL-XL inhibitors with other agents.

Main Methods:

  • Utilized SCLC as a model system to study protein expression and drug sensitivity.
  • Employed high-throughput screening to identify synergistic drug combinations.
  • Assessed the effects of inhibitors like ABT-263, doxorubicin, and dinaciclib on apoptosis pathways.

Main Results:

  • ABT-263 (navitoclax) efficacy was limited in cells with low activator BH3s and high BCL-XL, due to incomplete apoptosis induction.
  • Anthracyclines (doxorubicin) and CDK9 inhibitors (dinaciclib) synergized with ABT-263 by downregulating MCL-1.
  • Combinations of ABT-199 (venetoclax) with doxorubicin or dinaciclib showed promise for SCLC treatment.

Conclusions:

  • Mechanism-guided targeting of anti-apoptotic BCL-2 proteins is essential for activating mitochondrial cell death.
  • Understanding differential protein addiction in cancer cells can guide the development of effective combination therapies.
  • Targeting MCL-1 and BCL-XL concurrently with BCL-2 inhibitors offers a viable therapeutic strategy for SCLC.

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