Abstract 974: FAK inhibitors VS-6063 and VS-4718 target cancer stem cells: Implications for TNBC sequential and combination therapies

Abstract

Abstract Cancer stem cells (CSCs), a subpopulation of tumor cells characterized by tumor-initiating capability and resistance to chemotherapy, are an underlying cause of tumor progression and metastasis. In breast cancer, CSCs can be identified by aldehyde dehydrogenase 1 (ALDH) or CD44+/CD24- expression separately, although combination of ALDH, CD44+, and CD24- together may better describe the CSC population in breast cancer. Neoadjuvant chemotherapy has been shown to lead to an increase in CSCs in locally advanced breast cancer (Alamgeer et al., 2014, Br. Can. Res. 16:R14) which is associated with a significantly worse prognosis. It is also evident that stem-like features of tumor cells are present in metastatic breast cancer (Yu et al., 2013, Science 339:580) indicating that targeting of CSCs may be valuable in metastatic disease. VS-6063 and VS-4718 are orally bioavailable, potent and selective inhibitors of Focal Adhesion Kinase (FAK). These agents preferentially target CSCs in preclinical models and are currently in clinical development. Here we report that VS-6063 and VS-4718 preferentially target CSCs in multiple breast cancer models. Ex vivo treatment of explants from human breast tumors with either VS-6063 or VS-4718 decreased the proportion of CSCs in contrast to paclitaxel treatment which increased the proportion of CSCs. In an MDA-MB-231 mouse xenograft model, in vivo treatment with VS-6063 decreased CSCs by more than 6-fold as demonstrated by limiting dilution transplantation assay. Consistent with the notion that CSCs are responsible for cancer relapse after chemotherapy, VS-6063 and VS-4718 substantially delayed tumor growth following cessation of paclitaxel or cisplatin treatment in models of TNBC, including a patient-derived xenograft. Furthermore, using an imaging-based 4T1-luciferase TNBC orthotopic model, both VS-6063 and VS-4718 inhibited metastatic outgrowth or induced regression of metastases after primary tumor resection, whereas metastases progressed in all animals in the vehicle control group. A multiplex assay for multiple CSC markers (ALDH1, CD44 and CD24) was developed and validated in biopsies of primary patient tumors and matched lymph node biopsies taken pre- and post-neoadjuvant chemotherapy. CSCs, represented by the ALDH+ and/or CD44+/CD24- populations were present at detectable levels in a high fraction of triple negative breast cancer primary tumors. In summary, CSCs are readily detectable in primary breast cancers at surgery, and VS-6063 and VS-4718 diminish the CSC subpopulation in vitro, ex vivo and in xenograft models. This critical subpopulation of CSCs is detectable in residual tumors after neoadjuvant therapy, and may also be present in metastatic disease. CSC-targeted agents such as VS-6063 or VS-4718 should be clinically tested in these breast cancer settings to potentially delay time to relapse and improve patient outcome. Citation Format: Vihren N. Kolev, Kam Sprott, Qunli Xu, Jonathan A. Pachter, David T. Weaver. FAK inhibitors VS-6063 and VS-4718 target cancer stem cells: Implications for TNBC sequential and combination therapies. [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 974. doi:10.1158/1538-7445.AM2015-974