Selection Of Presumed Cd49f Antagonists And Their Biological Evaluation In Breast Cancer Cells

Breast cancer is the second cause of cancer death in women and the large majority of those deaths are due to drug resistance and/or recurrence. The cancer stem cell (CSC) model suggests that tumor stem-like cells play key roles in resistance and recurrence in breast cancer patients. Thus, CSCs have been pointed as targets for new anti-cancer therapies. CD49f is an integrin subunit that participates in the CSC-niche interaction. Knock-down of CD49f in breast cancer cells impairs mammosphere formation in vitro and tumorigenesis in vivo , suggesting that this protein is needed for maintenance of stemness. Aiming to target breast CSC, we used consensus docking to select potential CD49f antagonists from a collection of 13,000+ drugs with previous clinical evaluations. Seven compounds with the lowest consensus Z score were selected for in vitro biological validation. Cell adhesion assays showed that four of the selected drugs (5193, 1382, 7631, and 12723) decrease the binding of CD49f+ MDA-MB-231 breast cancer cells to laminin, suggesting that those compounds antagonize the receptor. Mammosphere formation assays showed that compounds 5193, 1382, and 12723 limit the clonogenic capability of CD49f+ breast cancer cells in vitro . Compound 5193 was highly toxic in 2D cell viability assays. On the other hand, the clonogenic impairment produced by compounds 1382 and 12723 is independent of bulk cell line cytotoxicity, suggesting a direct impact on the CSC pool. The analyses of the effect of these drugs on the expression of breast CSC markers and CD49f-activated pathways are on their way. Thus, we have identified some drugs that might be repurposed to target breast CSC. Since the pharmacokinetics and toxicology of those drugs is known, they could easily be ready for clinical trials. We demonstrated that in silico screening is useful to identify antagonists of receptors with relevant roles in breast CSC biology. This work was supported by CONACYT 221105, PAPIIT-UNAM IN228616, and Red tematica de celulas troncales y medicina regenerativa. Citation Format: Velasco-Velazquez M, Velazquez-Quesada I, Aguirre-Alvarado C, Guerrero-Rodriguez S, Ruiz-Moreno A, Ramirez-Salinas G, Segura-Cabrera A, Perez-Tapia M. Selection of presumed CD49f antagonists and their biological evaluation in breast cancer cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-06-09.