A synergistic anti-cancer FAK and HDAC inhibitor combination discovered by a novel chemical-genetic high-content phenotypic screen

John C Dawson, Bryan Serrels, Adam Byron, Morwenna T. Muir, Ashraff Makda, Amaya Garcia-Muñoz, Alex von Kriegsheim, Daniel Lietha, Neil O. Carragher, Margaret Frame

Research output: Contribution to journalArticlepeer-review

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 reexpressed mutant and wild-type 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 subset 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.
Original languageEnglish
Pages (from-to)637–649
Number of pages13
JournalMolecular Cancer Therapeutics
Volume19
Issue number2
Early online date29 Nov 2019
DOIs
Publication statusPublished - Feb 2020

Keywords

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

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