Tankyrase inhibition sensitizes cells to CDK4 blockade

Foronda, M., Tarumoto, Y., Schatoff, E. M., Leach, B. I., Diaz, B. J., Zimmerman, J., Goswami, S., Shusterman, M., Vakoc, C. R., Dow, L. E. (December 2019) Tankyrase inhibition sensitizes cells to CDK4 blockade. PLoS One, 14 (12). e0226645. ISSN 1932-6203

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Abstract

Tankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the ss-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition. We show that the loss of CDK4, but not CDK6, synergizes with TNKS1/2 blockade to drive G1 cell cycle arrest and senescence. Through precise modelling of cancer-associated mutations using cytidine base editors, we show that this therapeutic approach is absolutely dependent on suppression of canonical WNT signaling by TNKS inhibitors and is effective in cells from multiple epithelial cancer types. Together, our results suggest that combined WNT and CDK4 inhibition might provide a potential therapeutic strategy for difficult-to-treat epithelial tumors.

Item Type:	Paper
Subjects:	bioinformatics diseases & disorders bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics Investigative techniques and equipment diseases & disorders > neoplasms bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organs, tissues, organelles, cell types and functions > cell types and functions > cell functions organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types > cell line organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions > cell types organs, tissues, organelles, cell types and functions > cell types and functions Investigative techniques and equipment > CRISPR-Cas9 bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell organs, tissues, organelles, cell types and functions > cell types and functions > cell types > epithelial cell bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase organs, tissues, organelles, cell types and functions bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > senescence diseases & disorders > cancer > drugs and therapies > tumor microenvironment bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > Wnt
CSHL Authors:	Vakoc, Christopher R. Tarumoto, Yusuke
Communities:	CSHL labs > Vakoc lab CSHL Cancer Center Program > Cancer Genetics and Genomics Program
Depositing User:	Adrian Gomez
Date:	31 December 2019
Date Deposited:	06 Jan 2020 18:46
Last Modified:	02 Feb 2024 15:05
PMCID:	PMC6938305
Related URLs:	Publisher
URI:	https://repository.cshl.edu/id/eprint/38870

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