GYS1 inhibition and synthetic lethality with mitochondrial inhibitors in breast cancer
Session type: Poster / e-Poster / Silent Theatre session
Elevated glycogen levels and upregulation of key players in the glycogen metabolism are characteristics of various tumour types and associated with treatment resistance and poor clinical outcomes. We studied the role of glycogen synthase (GYS1) in breast cancer cell growth and metabolism, and evaluated its role in sensitivity to mitochondrial inhibitors.
Gene expression of key players in glycogen metabolism (including GYS1, GYS2 and glycogen phosphorylase [PYGL, PYGB]) was analysed in the METABRIC dataset, containing genomic and transcriptomic profiles of 2000 breast cancer cases. Using siRNAs targeting GYS1, the impact of acute GYS1 knockdown on proliferation was studied in a broad panel of breast cancer cell lines and in a spheroid model of the triple-negative cell line MDAMB231. shGYS1 breast cancer cell lines were used for a synthetic lethality screening with approved anti-cancer drugs and mitochondrial inhibitors with various mitochondrial targets.
High expression of GYS1 was correlated with poor survival in triple-negative breast cancer patients within the METABRIC data set. Downregulation of GYS1 significantly decreased cell growth of breast cancer cell lines BT474, SKBR3, MCF7, T47D, MDAMB453, MDAMB231, CAL51, MDAMB436, MDAMB468, HCC1143, HCC1937, HCC1806 (p<0.001, n=3) but not of SUM159PT. MDAMB231 spheroid growth was significantly impaired upon GYS1 inhibition (p<0.001, n=3). Finally, shGYS1 cancer cell lines were more sensitive to mitochondrial inhibitors (including gamitrinib-triphenylphosphonium and Novintum NBS037).
Inhibition of GYS1 decreases breast cancer cell proliferation and enhances the anti-cancer effect of mitochondrial inhibitors. Investigation of the underlying mechanism of action of this synthetic lethality is currently ongoing, and hypothesised to be related to changes in mitochondrial metabolism.