Inhibition of SYK kinase does not confer a pro-proliferative or pro-invasive phenotype in breast epithelium or breast cancer cells.

// David J. Lamb 1 , Aleksander Rust 2 , Albin Rudisch 3 , Tobias Gluxam 4 , Nathalie Harrer 3 , Herwig Machat 3 , Ingrid Christ 1 , Florian Colbatzky 5 , Andreas Wernitznig 3 , Annika Osswald 6 and Wolfgang Sommergruber 3 , 7 1 Immunology & Respiratory, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Ris, Germany 2 Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 3 Cancer Cell Signalling, Boehringer Ingelheim RCV GmbH & Co KG, A-1121 Vienna, Austria 4 Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, 1090 Wien, Austria 5 Non-clinical drug safety, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Ris, Germany 6 Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach an der Ris, Germany 7 Biotechnology, University of Applied Sciences, 1030 Vienna, Austria Correspondence to: David J. Lamb, email: david.lamb@boehringer-ingelheim.com Keywords: SYK inhibitor; breast carcinoma; 3D culture; murine mammary gland; proliferation Received: November 27, 2019     Accepted: March 14, 2020     Published: April 07, 2020 ABSTRACT SYK has been reported to possess both tumour promotor and repressor activities and deletion has been linked to a pro-proliferative / pro-invasive phenotype in breast tumours. It is unclear whether this is a consequence of protein deletion or loss of kinase activity. The SYK inhibitor, BI 1002494, caused no increase in proliferation in breast cancer cells or primary mammary epithelial cells in 2D or 3D cultures, nor changes in proliferation (CD1/2, CDK4, PCNA, Ki67) or invadopodia markers (MMP14, PARP, phospho-vimentin Ser56). BI 1002494 did not alter SYK protein expression. There was no change in phenotype observed in 3D cultures after addition of BI 1002494. Thirteen weeks of treatment with BI 1002494 resulted in no ductal branching or cellular proliferation in the mammary glands of mice. An in silico genetic analysis in breast tumour samples revealed no evidence that SYK has a typical tumour suppressor gene profile such as focal deletion, inactivating mutations or lower expression levels. Furthermore, SYK mutations were not associated with reduction in survival and disease-free period in breast cancer patients. In conclusion, small molecule inhibition of the kinase function of SYK does not contribute to a typical tumour suppressor profile.