Inhibition of the integrin/FAK signaling axis and c-Myc synergistically disrupts ovarian cancer malignancy

B. Xu, J. Lefringhouse, Z. Liu, D. West, L. A. Baldwin, C. Ou, L. Chen, D. Napier, L. Chaiswing, L. D. Brewer, D. St Clair, O. Thibault, J. R. Van Nagell, B. P. Zhou, R. Drapkin, J. A. Huang, M. L. Lu, F. R. Ueland, X. H. Yang

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish
Article numbere295
JournalOncogenesis
Volume6
Issue number1
DOIs
StatePublished - 2017

Bibliographical note

Funding Information:
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. Helen Yang edited the manuscript and Shengjie Wu assisted on the statistical analyses of experimental data.

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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