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Mol Syst Biol. 2015 Feb 19;11(1):789. doi: 10.15252/msb.20145664.

Targeting a cell state common to triple-negative breast cancers.

Author information

1
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
2
Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
3
University of Veterinary Medicine, Vienna, Austria.
4
Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
5
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
6
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria snijman@cemm.oeaw.ac.at.

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.

KEYWORDS:

breast cancer; cell state; small‐molecule screen

PMID:
25699542
PMCID:
PMC4358660
[Indexed for MEDLINE]
Free PMC Article

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