title: Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy.
abstract: Integrins, a family of heterodimeric receptors for extracellular matrix, are promising therapeutic targets for ovarian cancer, particularly high-grade serous-type (HGSOC), as they drive tumor cell attachment, migration, proliferation and survival by activating focal adhesion kinase (FAK)-dependent signaling. Owing to the potential off-target effects of FAK inhibitors, disruption of the integrin signaling axis remains to be a challenge. Here, we tackled this barrier by screening for inhibitors being functionally cooperative with small-molecule VS-6063, a phase II FAK inhibitor. From this screening, JQ1, a potent inhibitor of Myc oncogenic network, emerged as the most robust collaborator. Treatment with a combination of VS-6063 and JQ1 synergistically caused an arrest of tumor cells at the G2/M phase and a decrease in the XIAP-linked cell survival. Our subsequent mechanistic analyses indicate that this functional cooperation was strongly associated with the concomitant disruption of activation or expression of FAK and c-Myc as well as their downstream signaling through the PI3K/Akt pathway. In line with these observations, we detected a strong co-amplification or upregulation at genomic or protein level for FAK and c-Myc in a large portion of primary tumors in the TCGA or a local HGSOC patient cohort. Taken together, our results suggest that the integrin-FAK signaling axis and c-Myc synergistically drive cell proliferation, survival and oncogenic potential in HGSOC. As such, our study provides key genetic, functional and signaling bases for the small-molecule-based co-targeting of these two distinct oncogenic drivers as a new line of targeted therapy against human ovarian cancer.
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: B
authors.initials: B
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lefringhouse
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Jiangsu Province, PR China.
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: D
authors.initials: D
authors.lastname: West
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Baldwin
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ou
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: D
authors.initials: D
authors.lastname: Napier
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chaiswing
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Brewer
authors.affiliation: Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY, USA.
authors.forename: D
authors.initials: D
authors.lastname: St Clair
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: O
authors.initials: O
authors.lastname: Thibault
authors.affiliation: Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: van Nagell
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: B P
authors.initials: BP
authors.lastname: Zhou
authors.affiliation: Department of Gynecologic Cancer Research, Basser Center for BRCA, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Jiangsu Province, PR China.
authors.forename: J-A
authors.initials: JA
authors.lastname: Huang
authors.affiliation: Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Lu
authors.affiliation: Department of Obstetrics and Gynecology, University of Kentucky, Lexington, KY, USA.|Department of Pathology, University of Kentucky, Lexington, KY, USA.
authors.forename: F R
authors.initials: FR
authors.lastname: Ueland
authors.affiliation: Department of Pharmacology and Nutritional Science, University of Kentucky, Lexington, KY, USA.|Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA.|Markey Cancer Center, University of Kentucky, Lexington, KY, USA.|Department of Respiratory Medicine, First Affiliated Hospital of Soochow University, Jiangsu Province, PR China.
authors.forename: X H
authors.initials: XH
authors.lastname: Yang