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

Nat Commun. 2017 Jul 17;8:16078. doi: 10.1038/ncomms16078.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aniline Compounds / pharmacology
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / drug effects
  • Apoptosis Regulatory Proteins / metabolism
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase 9 / antagonists & inhibitors
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm
  • Drug Synergism
  • High-Throughput Screening Assays
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / metabolism*
  • Molecular Targeted Therapy
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
  • Myeloid Cell Leukemia Sequence 1 Protein / drug effects*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-bcl-2 / drug effects*
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyridinium Compounds / pharmacology
  • Small Cell Lung Carcinoma / drug therapy
  • Small Cell Lung Carcinoma / metabolism*
  • Sulfonamides / pharmacology
  • bcl-X Protein / antagonists & inhibitors
  • bcl-X Protein / drug effects*
  • bcl-X Protein / metabolism

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Apoptosis Regulatory Proteins
  • BCL2 protein, human
  • BCL2L1 protein, human
  • Bridged Bicyclo Compounds, Heterocyclic
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyridinium Compounds
  • Sulfonamides
  • bcl-X Protein
  • dinaciclib
  • Doxorubicin
  • Cyclin-Dependent Kinase 9
  • venetoclax
  • navitoclax