midostaurin and Triple-Negative-Breast-Neoplasms

Some mutations in cancer cells can be exploited for therapeutic intervention. However, for many cancer subtypes, including triple-negative breast cancer (TNBC), no frequently recurring aberrations could be identified to make such an approach clinically feasible. Characterized by a highly heterogeneous mutational landscape with few common features, many TNBCs cluster together based on their 'basal-like' transcriptional profiles. We therefore hypothesized that targeting TNBC cells on a systems level by exploiting the transcriptional cell state might be a viable strategy to find novel therapies for this highly aggressive disease. We performed a large-scale chemical genetic screen and identified a group of compounds related to the drug PKC412 (midostaurin). PKC412 induced apoptosis in a subset of TNBC cells enriched for the basal-like subtype and inhibited tumor growth in vivo. We employed a multi-omics approach and computational modeling to address the mechanism of action and identified spleen tyrosine kinase (SYK) as a novel and unexpected target in TNBC. Quantitative phosphoproteomics revealed that SYK inhibition abrogates signaling to STAT3, explaining the selectivity for basal-like breast cancer cells. This non-oncogene addiction suggests that chemical SYK inhibition may be beneficial for a specific subset of TNBC patients and demonstrates that targeting cell states could be a viable strategy to discover novel treatment strategies.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; Cell Survival; Drug Delivery Systems; Female; Gene Expression Profiling; Humans; Intracellular Signaling Peptides and Proteins; Mice; Molecular Docking Simulation; Molecular Targeted Therapy; Protein Interaction Domains and Motifs; Protein-Tyrosine Kinases; Proteomics; Sequence Analysis, RNA; Signal Transduction; STAT3 Transcription Factor; Staurosporine; Syk Kinase; Transforming Growth Factor beta; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays

Breast cancer is classified into three subtypes by the expression of biomarker receptors such as hormone receptors and human epidermal growth factor receptor 2. Triple-negative breast cancer (TNBC) expresses none of these receptors and has an aggressive phenotype with a poor prognosis, which is insensitive to the drugs that target the hormone receptors and human epidermal growth factor receptor 2. It is, thus, required to develop an effective therapeutic reagent to treat TNBC.. The study using a panel of 19 breast cancer cell lines revealed that midostaurin, a multi-target protein kinase inhibitor, suppresses preferentially the growth of TNBC cells comparing with non-TNBC cells. Clustering analysis of the drug activity data for the panel of cancer cell lines predicted that midostaurin shares the target with Aurora kinase inhibitors. Following studies indicated that midostaurin attenuates the phosphorylation reaction mediated by Aurora kinase in the cells and directly inhibits this protein kinase in vitro, and that this reagent induces apoptosis accompanying accumulation of 4N and 8N DNA cells in TNBC cells.. Midostaurin suppresses the proliferation of TNBC cells among the breast cancer cell lines presumably through the inhibition of the Aurora kinase family. The precise study of midostaurin on cell growth will contribute to the development of the drug for the treatment of TNBC.

Topics: Animals; Apoptosis; Aurora Kinase A; Aurora Kinase B; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice; Protein Kinase Inhibitors; Staurosporine; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays