A common cell state in Triple Negative Breast Cancers can be targeted through inhibition of Spleen Tyrosine Kinase (SYK)

ABSTRACT: Breast tumors are highly heterogeneous and for many molecular subtypes no targeted therapies are available. These include breast cancers that display hallmarks of epithelial to mesenchymal transition (EMT), a process related to metastasis and enriched in triple negative breast cancers (TNBCs). To determine whether this EMT cellular state could be therapeutically exploited, we performed a large-scale chemical genetic screen. We identified a group of structurally related compounds, including the clinically advanced drug PKC412 (midostaurin), that targeted post-EMT breast cancer cells. PKC412 induced apoptosis specifically in basal-like TNBC cells and inhibited tumor growth in vivo. Structure activity relationship (SAR) studies, chemical proteomics, and computational modeling identified the kinase SYK as a critical PKC412 target. Specific SYK inhibitors and PKC412 displayed a similar profile across a large panel of breast cancer cell lines, indicating a shared mode of action. Phosphoproteomics analysis revealed that SYK activates STAT3, and chemical or genetic inhibition of STAT3 resulted in cell death in basal-like breast cancer cells. This non-oncogene addiction of basal-like breast cancer cells to SYK suggests that chemical SYK inhibition may be beneficial for a specific subset of triple negative breast cancer patients.

OTHER RELATED OMICS DATASETS IN: PRJNA268911

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell

DISEASE(S): Breast Cancer

SUBMITTER: Andre Mueller  

LAB HEAD: Keiryn L. Bennett

PROVIDER: PXD001680 | Pride | 2016-06-15

REPOSITORIES: Pride