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

Dawson, J. C.; Serrels, B.; Byron, A.; Muir, M.; Makda, A.; Garcia-Munoz, A.; von Kriegsheim, A.; Carragher, N. O.; Frame, M. C.

doi:10.1101/590802

bioRxiv · 10.1101/590802

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

Dawson, J. C.·Serrels, B.·Byron, A.·Muir, M.·Makda, A.·Garcia-Munoz, A.·von Kriegsheim, A.·Carragher, N. O.·Frame, M. C.

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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 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. HDAC inhibitors represented the major class of compounds that potently induced multi-parametric phenotypic changes when FAK was rendered kinase-defective, or inhibited pharmacologically in SCC cells. Indeed, combined FAK and HDAC inhibitors arrest proliferation and induce apoptosis in a sub-set of cancer cell lines in vitro and efficiently inhibits tumor growth in vivo. Mechanistically, HDAC inhibitors potentiate inhibitor-induced FAK inactivation and reverses 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.\n\nSignificanceWe describe a chemical-genetic, high-content phenotypic screening approach to discover effective anti-cancer combinations of targeted therapeutics through which we identified a novel, synergistic and clinically actionable, combination of FAK and HDAC inhibitors.

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Dawson, J. C., Serrels, B., Byron, A., Muir, M., Makda, A., Garcia-Munoz, A., von Kriegsheim, A., Carragher, N. O., Frame, M. C.. 2019-03-27. A Synergistic Anti-Cancer FAK and HDAC Inhibitor Combination Discovered by a Novel Chemical-Genetic High Content Phenotypic Screen. https://doi.org/10.1101/590802

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