Focal Adhesion Kinase Inhibition Contributes to Tumor Cell Survival and Motility in Neuroblastoma Patient-Derived Xenografts.

Abstract

Patient-derived xenografts (PDXs) provide an opportunity to evaluate the effects of therapies in an environment that more closely resembles the human condition than that seen with long-term passage cell lines. In the current studies, we investigated the effects of FAK inhibition on two neuroblastoma PDXs in vitro. Cells were treated with two small molecule inhibitors of FAK, PF-573,228 (PF) and 1,2,4,5-benzentetraamine tetrahydrochloride (Y15). Following FAK inhibition, cell survival and proliferation decreased significantly and cell cycle arrest was seen in both cell lines. Migration and invasion assays were used to determine the effect of FAK inhibition on cell motility, which decreased significantly in both cell lines in the presence of either inhibitor. Finally, tumor cell stemness following FAK inhibition was evaluated with extreme limiting dilution assays as well as with immunoblotting and quantitative real-time PCR for the expression of stem cell markers. FAK inhibition decreased formation of tumorspheres and resulted in a corresponding decrease in established stem cell markers. FAK inhibition decreased many characteristics of the malignant phenotype, including cancer stem cell like features in neuroblastoma PDXs, making FAK a candidate for further investigation as a potential target for neuroblastoma therapy.

• Authors: Laura L Stafman, Adele P Williams, Raoud Marayati, Jamie M Aye, Hooper R Markert, Evan F Garner, Colin H Quinn, Shoeb B Lallani, Jerry E Stewart, Karina J Yoon, Kimberly Whelan, Elizabeth A Beierle
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 13259 (09 13 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31519958 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• 6-(4-(3-(methylsulfonyl)benzylamino)-5-(trifluoromethyl)pyrimidin-2-ylamino)-3,4-dihydroquinolin-2(1H)-one
• Quinolones
• Sulfones
• Focal Adhesion Kinase 1
• PTK2 protein, human

Topics

• Animals
• Apoptosis
• Cell Cycle
• Cell Movement
• Cell Proliferation
• Child
• Female
• Focal Adhesion Kinase 1 (antagonists & inhibitors)
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness
• Neuroblastoma (drug therapy, enzymology, pathology)
• Quinolones (pharmacology)
• Sulfones (pharmacology)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays