Abstract LB-60: Targeting stem cells in triple negative breast cancer through combined MEK and AKT inhibition

Abstract

Abstract Breast cancer stem cells (CSCs) are hypothesized to be involved in tumor metastasis, dormancy, and eventual recurrence. Among the molecular subtypes of breast cancer, triple negative (i.e. lacking HER2 amplification and estrogen and progesterone receptors) cancers have the highest frequency of CSCs with cytotoxic chemotherapy being the only established treatment option. Breast CSCs are relatively resistant to cytotoxic chemotherapy and radiation treatment indicating new treatment modalities are needed. Breast CSCs can be identified using flow cytometry with the cell surface marker profile CD44+CD24-EpCAM+ or by intracellular expression of aldehyde dehydrogenase (ALDH+). Previously, we identified a role for AKT signaling in the survival of breast CSCs. Here, we have tested if inhibition of MEK and AKT signaling with two small molecules, GSK1120212 and GSK690693, respectively, were able to reduce the frequency and overall number of CD44+CD24-EpCAM+ and/or ALDH+ CSCs in multiple triple-negative breast cancer cell lines. Our results suggest that either the CD44+CD24-EpCAM+ or ALDH+ fraction are sensitive to three days of combined inhibitor treatment. Within the MDA-MB-468 cell line, there is more phospho AKT (S473) and phospho MEK1/2 (S218/S222) signaling in both ALDH+ and CD44+CD24-EpCAM+ cells compared to non-stem cells. Furthermore, there is more phospho MEK1/2 in ALDH+ cells compared to CD44+CD24-EpCAM+ and more phospho AKT in CD44+CD24-EpCAM+ cells compared to ALDH+ CSCs. Together, these results highlight the possibility of using a combination of these agents in clinical trials to target triple-negative breast CSCs. Citation Format: Kevin Zhang, Sean P. McDermott, Max S. Wicha. Targeting stem cells in triple negative breast cancer through combined MEK and AKT inhibition. [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 LB-60. doi:10.1158/1538-7445.AM2014-LB-60