Abstract 796: Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy

Abstract

Abstract Detachment of cells from the extracellular matrix (ECM) results in a form of cell death referred to as anoikis. Anoikis resistance (AR), frequently acquired by malignant cells, is required for tumor metastases. The present study focused on identifying the mechanisms by which drug sensitivity is restored in previously resistant AR breast cancer cells. AR breast cancer cells display reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA and PUMA. In contrast, expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. It has previously been noted that AR cells display resistance to several currently available anti-tumor cell therapies, including a combinational approach with Lapatinib (ERBB1/2 inhibitor) and Obatoclax (MCL-1 inhibitor, exhibiting reduced autophagic flux, despite similarly exhibiting increased levels of LC3II processing. Knockdown of MCL-1 and BCL-XL in AR cells resulted in apoptosis to a greater extent than in their wild-type counterparts. Pre-treatment of AR cells with Valproate (histone deacetylase inhibitor (HDACIs)); for 24hrs increased the levels of toxic BH3 domain proteins whilst simultaneously reducing levels of MCL-1 and re-sensitising AR cells to therapy-mediated cell death. In vivo, pre-treatment of AR breast tumors in the brain with valproate restored chemo-sensitivity and prolonged animal survival. These data argue that pre-treatment with HDACIs may provide a mechanism to enhance the anti-tumor effect of chemotherapy in AR breast cancer cells. Citation Format: Nichola A. Cruickshanks, Hossein A. Hamed, Larry A. Booth, Seyedmehrad Tavallai, G B. Sajithlal, Steven Grant, Andrew Poklepovic, Paul Dent. Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis-resistant mammary and brain cancer stem cells, thereby enhancing the response to anti-ERBB1/ERBB2 therapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 796. doi:10.1158/1538-7445.AM2014-796