Precision Targeting of BFL-1/A1 and an ATM Co-dependency in Human Cancer

Cell Rep. 2018 Sep 25;24(13):3393-3403.e5. doi: 10.1016/j.celrep.2018.08.089.

Abstract

Cancer cells overexpress a diversity of anti-apoptotic BCL-2 family proteins, such as BCL-2, MCL-1, and BFL-1/A1, to enforce cellular immortality. Thus, intensive drug development efforts have focused on targeting this class of oncogenic proteins to overcome treatment resistance. Whereas a selective BCL-2 inhibitor has been FDA approved and several small molecule inhibitors of MCL-1 have recently entered phase I clinical testing, BFL-1/A1 remains undrugged. Here, we developed a series of stapled peptide design principles to engineer a functionally selective and cell-permeable BFL-1/A1 inhibitor that is specifically cytotoxic to BFL-1/A1-dependent human cancer cells. Because cancers harbor a diversity of resistance mechanisms and typically require multi-agent treatment, we further investigated BFL-1/A1 co-dependencies by mining a genome-scale CRISPR-Cas9 screen. We identified ataxia-telangiectasia-mutated (ATM) kinase as a BFL-1/A1 co-dependency in acute myeloid leukemia (AML), which informed the validation of BFL-1/A1 and ATM inhibitor co-treatment as a synergistic approach to subverting apoptotic resistance in cancer.

Keywords: A1; AML; ATM; BCL-2 family; BFL-1; apoptosis; cancer; covalent inhibitor; dependency; stapled peptide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Ataxia Telangiectasia Mutated Proteins / antagonists & inhibitors*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Binding Sites
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Female
  • HEK293 Cells
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Male
  • Minor Histocompatibility Antigens / chemistry
  • Minor Histocompatibility Antigens / metabolism
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / chemistry
  • Proto-Oncogene Proteins c-bcl-2 / metabolism

Substances

  • Antineoplastic Agents
  • BCL2-related protein A1
  • Minor Histocompatibility Antigens
  • Proto-Oncogene Proteins c-bcl-2
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins