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.
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Markus K
authors.initials: MK
authors.lastname: Muellner
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mair
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Yasir
authors.initials: Y
authors.lastname: Ibrahim
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kerzendorfer
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Hannelore
authors.initials: H
authors.lastname: Lechtermann
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Claudia
authors.initials: C
authors.lastname: Trefzer
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Freya
authors.initials: F
authors.lastname: Klepsch
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: André C
authors.initials: AC
authors.lastname: Müller
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Ernestine
authors.initials: E
authors.lastname: Leitner
authors.affiliation: University of Veterinary Medicine, Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Macho-Maschler
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Giulio
authors.identifier: http://orcid.org/0000-0002-0570-1768
authors.initials: G
authors.lastname: Superti-Furga
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Uwe
authors.initials: U
authors.lastname: Rix
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Stefan
authors.initials: S
authors.lastname: Kubicek
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Jacques
authors.initials: J
authors.lastname: Colinge
authors.affiliation: Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors.forename: Violeta
authors.initials: V
authors.lastname: Serra
authors.affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria snijman@cemm.oeaw.ac.at.
authors.forename: Sebastian M B
authors.initials: SM
authors.lastname: Nijman
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D054730:Protein Interaction Domains and Motifs; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000072377:Syk Kinase; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D016212:Transforming Growth Factor beta; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019311:Staurosporine; C059539:midostaurin
keywords: breast cancer; cell state; small‐molecule screen