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A Synergistic Anti-Cancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High-Content Phenotypic Screen

Research output: Contribution to journalArticle

Original languageEnglish
JournalMolecular Cancer Therapeutics
Early online date29 Nov 2019
DOIs
Publication statusE-pub ahead of print - 29 Nov 2019

Abstract

We mutated the focal adhesion kinase (FAK) catalytic domain to inhibit binding of the chaperone Cdc37 and ATP, mimicking the actions of a FAK kinase inhibitor. We re-expressed mutant and wildtype FAK in squamous cell carcinoma (SCC) cells from which endogenous FAK had been deleted, genetically fixing one axis of a FAK inhibitor combination high-content phenotypic screen to discover
drugs that may synergize with FAK inhibitors. Histone deacetylase (HDAC) inhibitors represented the major class of compounds that potently induced multiparametric phenotypic changes when FAK was rendered kinase-defective or inhibited pharmacologically in SCC cells. Combined FAK and HDAC inhibitors arrest proliferation and induce apoptosis in a sub-set of cancer cell lines in vitro and efficiently inhibit their growth as tumors in vivo. Mechanistically, HDAC inhibitors potentiate inhibitor-induced FAK inactivation and impair FAK-associated nuclear YAP in sensitive cancer cell lines. Here we report the discovery of a new, clinically actionable, synergistic combination between
FAK and HDAC inhibitors.

    Research areas

  • Focal Adhesion Inase, Histone Deacetylase, Inhibitor, Drug Combination, Cancer, High-Content Phenotypic Screening

ID: 119145708