Targeting BCL-2 With the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer

Cancer Cell. 2013 Jul 8;24(1):120-9. doi: 10.1016/j.ccr.2013.06.002.

Abstract

The prosurvival protein BCL-2 is frequently overexpressed in estrogen receptor (ER)-positive breast cancer. We have generated ER-positive primary breast tumor xenografts that recapitulate the primary tumors and demonstrate that the BH3 mimetic ABT-737 markedly improves tumor response to the antiestrogen tamoxifen. Despite abundant BCL-XL expression, similar efficacy was observed with the BCL-2 selective inhibitor ABT-199, revealing that BCL-2 is a crucial target. Unexpectedly, BH3 mimetics were found to counteract the side effect of tamoxifen-induced endometrial hyperplasia. Moreover, BH3 mimetics synergized with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors in eliciting apoptosis. Importantly, these two classes of inhibitor further enhanced tumor response in combination therapy with tamoxifen. Collectively, our findings provide a rationale for the clinical evaluation of BH3 mimetics in therapy for breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biphenyl Compounds / pharmacology
  • Breast Neoplasms / chemistry
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / pathology
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Female
  • Humans
  • Mice
  • Mice, SCID
  • Nitrophenols / pharmacology
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines / pharmacology
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Receptors, Estrogen / analysis*
  • Sulfonamides / pharmacology*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • Xenograft Model Antitumor Assays

Substances

  • ABT-737
  • Biphenyl Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Nitrophenols
  • Phosphoinositide-3 Kinase Inhibitors
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Receptors, Estrogen
  • Sulfonamides
  • TOR Serine-Threonine Kinases
  • venetoclax