Targeting a cell state common to triple‐negative breast cancers
| Autor: | Muellner, M. K., Mair, B., Ibrahim, Y., Kerzendorfer, C., Lechtermann, H., Trefzer, C., Klepsch, F., Muller, A. C., Leitner, E., Macho-Maschler, S., Superti-Furga, G., Bennett, K. L., Baselga, J., Rix, U., Kubicek, S., Colinge, J., Serra, V., Nijman, S. M. |
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| Přispěvatelé: | CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria, Vall d'Hebron Institute of Oncology [Barcelone] (VHIO), Vall d'Hebron University Hospital [Barcelona], Memorial Sloane Kettering Cancer Center [New York], H. Lee Moffitt Cancer Center and Research Institute, Institut de Recherche en Cancérologie de Montpellier (IRCM - U1194 Inserm - UM), CRLCC Val d'Aurelle - Paul Lamarque-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), KARLI, Mélanie |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Proteomics
STAT3 Transcription Factor Cell Survival Antineoplastic Agents Apoptosis Triple Negative Breast Neoplasms [SDV.CAN]Life Sciences [q-bio]/Cancer Mice Drug Delivery Systems breast cancer [SDV.CAN] Life Sciences [q-bio]/Cancer small-molecule screen Transforming Growth Factor beta Cell Line Tumor Animals Humans Syk Kinase Protein Interaction Domains and Motifs Molecular Targeted Therapy Cell Proliferation Sequence Analysis RNA Gene Expression Profiling Intracellular Signaling Peptides and Proteins Cell Differentiation Articles Protein-Tyrosine Kinases Staurosporine Xenograft Model Antitumor Assays small‐molecule screen Molecular Docking Simulation Female cell state Signal Transduction |
| Zdroj: | Molecular Systems Biology Molecular Systems Biology, EMBO Press, 2015, 11 (2), pp.789. ⟨10.15252/msb.20145664⟩ |
| ISSN: | 1744-4292 |
| DOI: | 10.15252/msb.20145664⟩ |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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