Abstract B07: Mcl-1-mediated resistance to ABT-263 is combated by mTOR inhibition in luminal breast cancers

Abstract

Abstract In the context of cancer, the intrinsic apoptotic pathway is exploited to favor tumor cell survival through overexpression of anti-apoptotic Bcl-2 family members (Bcl-A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1). We investigated targeting of anti-apoptotic Bcl-2 proteins in a panel of human luminal breast cancer cell lines. Use of ABT-263, the Bcl-2/Bcl-xL/Bcl-w inhibitor, induced transient tumor cell killing and decreased tumor cell growth in only 1 of 4 cell lines in three dimensional (3D) cultures. Mcl-1 expression and activity were rapidly upregulated upon ABT-263 treatment, highlighting the compensatory nature of Mcl-1. In luminal breast cancers, Mcl-1 was the most frequently amplified anti-apoptotic Bcl-2 family member according to The Cancer Genome Atlas, while nearly 80% of the luminal breast tumor epithelium was positive for Mcl-1 in a tissue microarray. Thus, we hypothesized that Mcl-1 may be a dominant tumor cell survival factor in luminal breast cancers. Use of the mTOR inhibitor RAD001 (everolimus) to target Mcl-1 indirectly decreased tumor cell growth and increased tumor cell killing in 3 of 4 cell lines, as well as WAP-Myc luminal mammary tumors, demonstrating the effectiveness of Mcl-1 as a therapeutic target in breast cancers. While Mcl-1 inhibition alone did not affect growth of T47D cells, robust growth inhibition and tumor cell killing were seen in all cell lines upon inhibition of Mcl-1 using RAD001 or a EIF4 complex inhibitor (4E1RCat) in combination with ABT-263, suggesting that the induction of Mcl-1 upon ABT-263 treatment may be supported by increased cap-dependent translation. These results demonstrate that the sensitivity of luminal breast cancers to ABT-263 is enhanced by Mcl-1 inhibition, warranting further investigation into inhibition of anti-apoptotic Bcl-2 family proteins, in particular Mcl-1, as a clinical strategy to improve survival of patients with luminal breast cancers. Citation Format: Michelle M. Williams, Linus Lee, Meghan M. Morrison, Courtney McKernan, Violeta Sanchez, Donna Hicks, Thomas Stricker, Rebecca S. Cook. Mcl-1-mediated resistance to ABT-263 is combated by mTOR inhibition in luminal breast cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B07.