Abstract B108: The novel HDAC inhibitor PCI-24781 synergizes with tamoxifen in ER-positive breast cancer by concertedly downregulating AKT1 expression.

Abstract

Abstract Breast cancer continues to be the most frequently diagnosed malignancy in women, and is second only to lung cancer as the cause of cancer death. While aromatase inhibitors are more commonly used in postmenopausal women, tamoxifen remains the only approved hormonal therapy for premenopausal patients presenting with estrogen receptor (ER)-positive disease. However, the effectiveness of tamoxifen is limited, as many tumors develop resistance. As such, substantial effort has been made to improve and extend the effectiveness of tamoxifen. To this end, we have demonstrated that histone deacetylase (HDAC) inhibitors potentiate the anti-tumor activity of tamoxifen in preclinical models, and in an early phase trial durable responses were achieved in a heavily pre-treated patient cohort. Mechanistic studies have revealed that HDAC inhibition directs breast cancer cells into mitochondrial-mediated apoptosis in part by altering the balance of apoptotic gatekeepers (e.g. Bax, Bak, and Bcl-2). In the current study, we extend our mechanistic understanding of this combination in ER-positive cells using the novel hydroxamic acid type HDAC inhibitor PCI-24781. Early clinical evaluation suggests that PCI-24781 is a potent HDAC inhibitor and is well tolerated at doses exceeding those needed for preclinical synergy. Here we demonstrate that PCI-24781 and tamoxifen act individually to additively abrogate AKT cell signaling by down regulating AKT1 mRNA and protein expression. Furthermore, PCI-24781 represses ESR1 transcription and thus exerts its effect on AKT1 expression in part through the regulation of ER expression. Attenuated AKT signaling manifests in elevated GSK3α/β phosphorylation, Bim, and p21 and a reduction in cyclin D. Cells exhibit an induction of an array of pro-apoptotic drivers, mitochondrial release of cytochrome C, caspase activation, and cell death. These results suggest that HDACs regulate the response of AKT to tamoxifen and that the cooperative effects of HDAC inhibitors and tamoxifen lead to enhance cell death. Therefore, early introduction of an HDAC inhibitor into hormonal therapy in patients with ER-positive breast cancer may counter the emergence of tamoxifen resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B108.