Targeting a cell state common to triple-negative breast cancers Journal Article
| Authors: | Muellner, M. K.; Mair, B.; Ibrahim, Y.; Kerzendorfer, C.; Lechtermann, H.; Trefzer, C.; Klepsch, F.; Müller, 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. B. |
| Article Title: | Targeting a cell state common to triple-negative breast cancers |
| Abstract: | 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. © 2015 The Authors. Published under the terms of the CC BY 4.0 license. |
| Keywords: | signal transduction; controlled study; unclassified drug; mutation; sunitinib; nonhuman; animal cell; mouse; animal tissue; cell viability; stat3 protein; apoptosis; breast cancer; tumor volume; transforming growth factor beta; animal experiment; animal model; in vivo study; in vitro study; drug specificity; drug synthesis; structure activity relation; proteomics; drug mechanism; epigenetics; quantitative analysis; western blotting; long term care; target cell; down regulation; high performance liquid chromatography; tumor growth; molecular docking; genetic screening; drug sensitivity; synthesis; rna sequence; phase 1 clinical trial (topic); triple negative breast cancer; affinity chromatography; midostaurin; tandutinib; 1 cyclopropyl 3 [3 (5 morpholinomethyl 1h benzimidazol 2 yl) 1h pyrazol 4 yl]urea; crystal violet; drug sensitization; cancer graft; basal like breast cancer; human; female; priority journal; article; cell state; small-molecule screen; fostamatinib; masitinib; osi 930; ruboxistaurin; tozasertib |
| Journal Title: | Molecular Systems Biology |
| Volume: | 11 |
| Issue: | 2 |
| ISSN: | 1744-4292 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2015-02-19 |
| Start Page: | 789 |
| Language: | English |
| DOI: | 10.15252/msb.20145664 |
| PROVIDER: | scopus |
| PMCID: | PMC4358660 |
| PUBMED: | 25699542 |
| DOI/URL: | |
| Notes: | Export Date: 2 April 2015 -- Source: Scopus |
