Combination mTORC1/2 and BCL- XL inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer.
Sammons, S; Anderson, G; Wardell, S; McDonnell, DP; Marcom, PK; Wood, K
Published in: Journal of Clinical Oncology
e14653 Background: Endocrine therapy plus CDK 4/6 inhibition has led to impressive improvements in progression-free survival in patients with advanced, estrogen receptor positive (ER+)/HER2-negative (HER2-) breast cancer. Resistance inevitably emerges, leaving patients with few proven therapeutic options. Our group has recently found that treatment of PIK3CA mutant ER+/HER2- breast cancer with inhibitors of mTORC1/2 and BCL-X causes impressive synergistic growth suppression and apoptosis induction compared to either agent alone in vitro and in vivo. We sought to assess activity in clinically relevant models of PIK3CA mutant ER+ breast cancer with acquired resistance to endocrine therapy and CDK4/6 inhibition. Methods: Using orthotopic MCF-7 xenograft tumors (ER+/ PIK3CA mutant) that were evolved through serial passaging in vivo to develop tamoxifen resistance (TamR), we developed models of resistant disease. TamR xenograft- bearing mice were then treated for 4-6 weeks with palbociclib (50 mg/kg qd), fulvestrant (100mg/kg qw), or the combination. Mice in each treatment group were divided into two groups following the initial development of resistance, defined by steady growth for 1-2 weeks: one receiving vehicle and the other receiving low dose MLN0128 0.3 mg/kg qd (mTORC1/2 inhibitor) + ABT-737 25 mg/kg qd (BCL-X /BCL-2 inhibitor). Results: Combination BCL-X (ABT-737) + mTORC1/2 (MLN0128) inhibition significantly inhibited growth in tamoxifen (p = 0.0045), fulvestrant/tamoxifen (p = 0.0035), palbociclib/tamoxifen (p = 0.0155), and palbociclib/tamoxifen/fulvestrant (0.005) resistant tumors compared to controls. These results were observed without significant animal toxicity, dose-limiting thrombocytopenia secondary to BCL-X inhibition, or toxicity to normal breast epithelial cells. We have observed tumor regressions in multiple models using doses five- to 12-fold lower than the equivalent doses required to cause clinically meaningful thrombocytopenia in humans and large animal models. Conclusions: Our data establish the rationale for investigating the combination of BCL-X and mTORC1/2 inhibition in a clinical trial of advanced PIK3CA mutant, ER+/HER2- breast cancer after progression on CDK 4/6 and endocrine therapy. Preclinical work is ongoing with novel inhibitors of BCL-X
