We found that 8.1% of luminal breast cancer cases curated by The Cancer Genome Atlas (TCGA), harbor gene amplification of anti-apoptotic Bcl-2 family members, warranting further study of anti-apoptotic Bcl-2 family proteins (A1, Bcl-2, Bcl-xL, Bcl-w and Mcl-1) in luminal breast cancers. A complex balance of pro- and anti-apoptotic Bcl-2 proteins guides activation versus repression of the intrinsic apoptotic pathway, with overexpression of anti-apoptotic factors tipping the balance towards cell survival. This mechanism is commonly used by cancers to evade apoptosis.

We used the BH3-mimetic ABT-263 to inhibit Bcl-2, Bcl-xL and Bcl-w in a panel of human luminal breast cancer lines, causing only modest apoptosis in monolayer and growth inhibition in three-dimensional (3D) matrix. Expression and activity of Mcl-1, another anti-apoptotic Bcl-2 family member, was rapidly upregulated in response to ABT-263 through increased cap-dependent MCL1 translation. Mcl-1 knock-down decreased tumor cell growth and improved ABT-263-mediated tumor cell killing. Inhibition of cap-dependent translation using the mTOR inhibitor RAD001/everolimus or the EIF4 complex inhibitor 4E1RCat blocked Mcl-1 induction in ABT-263 treated cells, enhancing apoptosis and growth inhibition. In vivo, single agent ABT-263 was ineffective at reducing tumor growth in xenografted human breast cancers and in transgenic WAP-Myc luminal mammary tumors. However, RAD001 decreased Mcl-1 levels and decreased WAP-Myc tumor growth by 40%. These results demonstrate that heightened cap-dependent translation of Mcl-1 prevents therapeutically induced tumor cell killing in ABT-263 treated luminal tumors, highlighting the importance of Mcl-1 regulation in therapeutic resistance, and identifying Mcl-1 as a potential therapeutic target in luminal breast cancers. These studies suggest that targeted inhibition of Mcl-1 alone or in combination with other Bcl-2 family inhibitors will enhance tumor cell killing in luminal breast cancers.

Citation Format: Michelle M. Williams, Linus Lee, Violeta Sanchez, Meghan M. Morrison, Donna Hicks, Rebecca S. Cook. Mcl-1-mediated resistance to ABT-263 is combated by mTOR inhibition in luminal breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5. doi:10.1158/1538-7445.AM2015-5

©2015 American Association for Cancer Research.
2015