Open AccessTargeting a cell state common to triple‐negative breast cancers
Author(s) -
Muellner Markus K,
Mair Barbara,
Ibrahim Yasir,
Kerzendorfer Claudia,
Lechtermann Hannelore,
Trefzer Claudia,
Klepsch Freya,
Müller André C,
Leitner Ernestine,
MachoMaschler Sabine,
SupertiFurga Giulio,
Bennett Keiryn L,
Baselga José,
Rix Uwe,
Kubicek Stefan,
Colinge Jacques,
Serra Violeta,
Nijman Sebastian MB
Publication year - 2015
Publication title -
molecular systems biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 8.523
H-Index - 148
ISSN - 1744-4292
DOI - 10.15252/msb.20145664
Subject(s) - triple negative breast cancer , biology , syk , cancer research , phosphoproteomics , cancer , breast cancer , tyrosine kinase , kinase , signal transduction , genetics , protein kinase a , protein phosphorylation
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 TNBC s 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 PKC 412 (midostaurin). PKC 412 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 STAT 3, 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.