| Added by | mollevi |
|---|---|
| Last modified by | jacques.colinge |
| Group name | EquipeJC |
| Item Type | Journal Article |
| Title | Targeting a cell state common to triple-negative breast cancers |
| Creator | Muellner et al. |
| Author | M. K. Muellner |
| Author | B. Mair |
| Author | Y. Ibrahim |
| Author | C. Kerzendorfer |
| Author | H. Lechtermann |
| Author | C. Trefzer |
| Author | F. Klepsch |
| Author | A. C. Muller |
| Author | E. Leitner |
| Author | S. Macho-Maschler |
| Author | G. Superti-Furga |
| Author | K. L. Bennett |
| Author | J. Baselga |
| Author | U. Rix |
| Author | S. Kubicek |
| Author | J. Colinge |
| Author | V. Serra |
| Author | S. M. Nijman |
| 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. |
| Publication | Mol Syst Biol |
| Volume | 11 |
| Pages | 789 |
| Date | Jan 2015 |
| Journal Abbr | Molecular systems biology |
| DOI | 10.15252/msb.20145664 |
| ISSN | 1744-4292 (Electronic) 1744-4292 (Linking) |
| Tags | original |
| Date Added | 2018/11/14 - 11:48:35 |
| Date Modified | 2019/09/14 - 15:53:05 |
| Notes and Attachments | (Note) (Note) 25699542 (Attachment) |
Institut de Recherche en Cancérologie de
