Projects per year
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 language | English |
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Pages (from-to) | 637–649 |
Number of pages | 13 |
Journal | Molecular Cancer Therapeutics |
Volume | 19 |
Issue number | 2 |
Early online date | 29 Nov 2019 |
DOIs | |
Publication status | Published - Feb 2020 |
Keywords / Materials (for Non-textual outputs)
- Focal Adhesion Inase
- Histone Deacetylase
- Inhibitor
- Drug Combination
- Cancer
- High-Content Phenotypic Screening
Fingerprint
Dive into the research topics of 'A synergistic anti-cancer FAK and HDAC inhibitor combination discovered by a novel chemical-genetic high-content phenotypic screen'. Together they form a unique fingerprint.Projects
- 3 Finished
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Expoiting adhesion protein networks in glioblastoma
Frame, M. (Principal Investigator), Brunton, V. (Co-investigator), Byron, A. (Co-investigator) & Pollard, S. (Co-investigator)
1/05/18 → 30/04/23
Project: Research
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Invasion and metastasis; understanding and targeting an adhesion protein network - Programme Grant Renewal
Frame, M. (Principal Investigator)
1/05/13 → 31/08/18
Project: Research
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Equipment
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Edinburgh Drug Discovery
Unciti-Broceta, A. (Manager), Webster, S. (Manager) & Carragher, N. (Manager)
Deanery of Molecular, Genetic and Population Health SciencesFacility/equipment: Facility
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Institute for Genetics and Cancer Mass Spectrometry Facility
Von Kriegsheim, A. (Manager)
Deanery of Molecular, Genetic and Population Health SciencesFacility/equipment: Facility
Profiles
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Neil Carragher
- Edinburgh Cancer Research Centre
- Institute of Genetics and Cancer - Personal Chair of Drug Discovery
Person: Academic: Research Active