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.
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This study was supported in part by a pilot project grant from American Cancer Society #IRG 85-001-25 and an industry fund from Beijing Yu-Jin Limited to XHY and 1R15CA143816 to MLU.
Supplementary Information accompanies this paper on the Oncogenesis website (http://www.nature.com/oncsis).
Xu, B.; Lefringhouse, Jason R.; Liu, Z.; West, D.; Baldwin, Lauren A.; Ou, C.; Chen, L.; Napier, Dana L.; Chaiswing, Luksana; Brewer, Lawrence D.; St Clair, Daret K.; Thibault, Olivier; van Nagell, John R.; Zhou, Binhua P.; Drapkin, R.; Huang, J. -A.; Lu, M. L.; Ueland, Frederick R.; and Yang, X. H., "Inhibition of the Integrin/FAK Signaling Axis and c-Myc Synergistically Disrupts Ovarian Cancer Malignancy" (2017). Pharmacology and Nutritional Sciences Faculty Publications. 53.