Focal adhesion kinase (FAK) inhibitors VS-6063 and VS-4718 target cancer stem cells
| Autor: | Vihren N. Kolev, Mahesh Padval, Mitchell Keegan, Qunli Xu, Christian M. Vidal, Joanna Horobin, Irina M. Shapiro, Daniel Paterson, Jonathan A. Pachter, Quentin G. Wright |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Journal of Clinical Oncology. 31:e13523-e13523 |
| ISSN: | 1527-7755 0732-183X |
| Popis: | e13523 Background: Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that orchestrates cellular signaling through integrins and growth factor receptors and functions in multiple steps of tumorigenesis. Both VS-6063 and VS-4718 are potent, selective, and orally active FAK inhibitors. In a phase I clinical trial, VS-6063 was well tolerated and demonstrated preliminary clinical activity. VS-4718 is in late stage preclinical development and has been shown to inhibit tumor growth and metastasis in tumor models. We report here that the FAK inhibitors VS-6063 and VS-4718 effectively abrogate cancer stem cells (CSCs). Methods: VS-6063 and VS-4718 were evaluated in the ALDEFLUOR and Side Population (SP) CSC assays in vitro and in xenograft tumors in vivo. Results: Treating SUM159 breast cancer cells with FAK inhibitors reduced the percentage of ALDEFLUOR+ and SP CSCs. Similar inhibitory effects on CSCs were observed in the ovarian cancer cell lines OVCAR-5 and OVCAR-8 and the mesothelioma cell line H2052. In direct contrast, cytotoxic agents paclitaxel, carboplatin and pemetrexed increased the percentage of CSCs, suggesting that these agents do not effectively target CSCs. Importantly, combination of either VS-6063 or VS-4718 with cytotoxic agents blocked induction of CSCs by these agents. The effect of a FAK inhibitor on CSCs in vivo was evaluated in an MDA-MB-231 human breast cancer orthotopic model. Oral administration of FAK inhibitor substantially reduced the number of ALDH1- positive cells in tumors as assessed by immunofluorescence. Following dissociation of cells from tumors, CSCs were found to be reduced in FAK inhibitor-treated tumors as measured by multiple assays. Furthermore, cells isolated from FAK inhibitor-treated tumors showed reduced tumor-initiating capability upon re-implantation into immunodeficient mice. FAK inhibitor also decreased ALDH1-positive CSCs in an orthotopic MM87 mesothelioma model. Conclusions: Our results provide clear demonstration that FAK inhibitors target cancer stem cells both in vitro and in xenograft tumors in vivo and support the planned clinical development of VS-6063 and VS-4718 to achieve durable clinical responses for cancer patients. |
| Databáze: | OpenAIRE |
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