Tankyrase inhibition sensitizes cells to CDK4 blockade


Autoři: Miguel Foronda aff001;  Yusuke Tarumoto aff002;  Emma M. Schatoff aff001;  Benjamin I. Leach aff001;  Bianca J. Diaz aff001;  Jill Zimmerman aff001;  Sukanya Goswami aff001;  Michael Shusterman aff001;  Christopher R. Vakoc aff002;  Lukas E. Dow aff001
Působiště autorů: Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States of America aff001;  Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America aff002;  Tri-Institutional MD-PhD program, Weill Cornell Medicine, New York, NY, United States of America aff003;  Department of Medicine, Weill Cornell Medicine, New York, NY, United States of America aff004;  Department of Biochemistry, Weill Cornell Medicine, New York, NY, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: 10.1371/journal.pone.0226645

Souhrn

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.

Klíčová slova:

Cell cycle and cell division – Cell cycle inhibitors – Colorectal cancer – Fluorescence competition – Guide RNA – Signal inhibition – Wnt signaling cascade


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