Targeting BCL-2 with the BH3 Mimetic ABT-199 in Estrogen Receptor-Positive Breast Cancer
Menée à l'aide de xénogreffes, cette éutde met en évidence l'intérêt d'un composé appelé ABT-737, un mimétique de BH3, en combinaison avec le tamoxifène pour le traitement de patientes atteintes d'un cancer du sein ER+
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.
"BH3 mimetics improve response of breast tumor xenografts to endocrine therapy
"The efficacy of the BCL-2-selective inhibitor ABT-199 reveals BCL-2 as a key target
"Synergy with PI3K/mTOR inhibitors reveals additional combinatorial therapy options
"BCL-2 inhibitors counteract tamoxifen-induced endometrial hyperplasia
Cancer cell , résumé, 2012