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

Muellner MK, Mair B, Ibrahim Y, Kerzendorfer C, Lechtermann H, Trefzer C, Klepsch F, Müller AC, Leitner E, Macho-Maschler S, Superti-Furga G, Bennett KL, Baselga J, Rix U, Kubicek S, Colinge J, Serra V, Nijman SM - Mol. Syst. Biol. (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus

A small-molecule screen identifies PKC412 as a post-EMT breast cancer cell-specific drugA Structural clustering of 104 compounds specifically toxic to MCF10A-Twist1 cells by Tanimoto/Jaccard index. Clusters were selected based on the indicated cutoff (dotted line), and those containing two or more structurally related compounds are highlighted. Compounds clustered with low confidence (based on visual inspection) are indicated by a red asterisk. The chemical structures of the staurosporine-like compound cluster are indicated (orange).B MMEC-HRASV12G cells treated with TGF-β (10 ng/μl) or vehicle for 14 days to induce a mesenchymal phenotype. Scale bar corresponds to 20 μm.C PKC412 dose–response curves of cells as in (B) after which TGF-β was washed out for 3 days, and cells with continuous TGF-β treatment for 17 days. Error bars indicate standard deviation. n = 3.D Crystal violet stain of cells from (B) treated with PKC412 (500 nM) for 7 days.E Dose–response curves of control MMEC-HRASV12G cells or MMEC-HRASV12G cells that have undergone EMT in vivo (XT) treated with PKC412 for 3 days. Error bars indicate standard deviation. n = 3.
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fig01: A small-molecule screen identifies PKC412 as a post-EMT breast cancer cell-specific drugA Structural clustering of 104 compounds specifically toxic to MCF10A-Twist1 cells by Tanimoto/Jaccard index. Clusters were selected based on the indicated cutoff (dotted line), and those containing two or more structurally related compounds are highlighted. Compounds clustered with low confidence (based on visual inspection) are indicated by a red asterisk. The chemical structures of the staurosporine-like compound cluster are indicated (orange).B MMEC-HRASV12G cells treated with TGF-β (10 ng/μl) or vehicle for 14 days to induce a mesenchymal phenotype. Scale bar corresponds to 20 μm.C PKC412 dose–response curves of cells as in (B) after which TGF-β was washed out for 3 days, and cells with continuous TGF-β treatment for 17 days. Error bars indicate standard deviation. n = 3.D Crystal violet stain of cells from (B) treated with PKC412 (500 nM) for 7 days.E Dose–response curves of control MMEC-HRASV12G cells or MMEC-HRASV12G cells that have undergone EMT in vivo (XT) treated with PKC412 for 3 days. Error bars indicate standard deviation. n = 3.

Mentions: As an initial validation step, we investigated whether specific chemical scaffolds were enriched among the hits using unsupervised clustering of Tanimoto/Jaccard indices for structural similarity, followed by visual inspection. This revealed a group of highly related compounds resembling the natural alkaloid staurosporine (Fig 1A). Staurosporine and many of its derivatives are potent broad-spectrum kinase inhibitors and have been investigated for the treatment of a variety of diseases, including cancer. One such derivative, PKC412 (midostaurin), has advanced into phase III clinical trials for the treatment of acute myeloid leukemia (AML) expressing the mutant tyrosine kinase receptor FLT3/CD135, itself a PKC412 target (Fischer et al, 2010). Like staurosporine, PKC412 is a multi-target protein kinase inhibitor and has been shown to have low nanomolar activity against additional kinases including c-KIT, PDGFR and several PKC family members.


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

Muellner MK, Mair B, Ibrahim Y, Kerzendorfer C, Lechtermann H, Trefzer C, Klepsch F, Müller AC, Leitner E, Macho-Maschler S, Superti-Furga G, Bennett KL, Baselga J, Rix U, Kubicek S, Colinge J, Serra V, Nijman SM - Mol. Syst. Biol. (2015)

A small-molecule screen identifies PKC412 as a post-EMT breast cancer cell-specific drugA Structural clustering of 104 compounds specifically toxic to MCF10A-Twist1 cells by Tanimoto/Jaccard index. Clusters were selected based on the indicated cutoff (dotted line), and those containing two or more structurally related compounds are highlighted. Compounds clustered with low confidence (based on visual inspection) are indicated by a red asterisk. The chemical structures of the staurosporine-like compound cluster are indicated (orange).B MMEC-HRASV12G cells treated with TGF-β (10 ng/μl) or vehicle for 14 days to induce a mesenchymal phenotype. Scale bar corresponds to 20 μm.C PKC412 dose–response curves of cells as in (B) after which TGF-β was washed out for 3 days, and cells with continuous TGF-β treatment for 17 days. Error bars indicate standard deviation. n = 3.D Crystal violet stain of cells from (B) treated with PKC412 (500 nM) for 7 days.E Dose–response curves of control MMEC-HRASV12G cells or MMEC-HRASV12G cells that have undergone EMT in vivo (XT) treated with PKC412 for 3 days. Error bars indicate standard deviation. n = 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4358660&req=5

fig01: A small-molecule screen identifies PKC412 as a post-EMT breast cancer cell-specific drugA Structural clustering of 104 compounds specifically toxic to MCF10A-Twist1 cells by Tanimoto/Jaccard index. Clusters were selected based on the indicated cutoff (dotted line), and those containing two or more structurally related compounds are highlighted. Compounds clustered with low confidence (based on visual inspection) are indicated by a red asterisk. The chemical structures of the staurosporine-like compound cluster are indicated (orange).B MMEC-HRASV12G cells treated with TGF-β (10 ng/μl) or vehicle for 14 days to induce a mesenchymal phenotype. Scale bar corresponds to 20 μm.C PKC412 dose–response curves of cells as in (B) after which TGF-β was washed out for 3 days, and cells with continuous TGF-β treatment for 17 days. Error bars indicate standard deviation. n = 3.D Crystal violet stain of cells from (B) treated with PKC412 (500 nM) for 7 days.E Dose–response curves of control MMEC-HRASV12G cells or MMEC-HRASV12G cells that have undergone EMT in vivo (XT) treated with PKC412 for 3 days. Error bars indicate standard deviation. n = 3.
Mentions: As an initial validation step, we investigated whether specific chemical scaffolds were enriched among the hits using unsupervised clustering of Tanimoto/Jaccard indices for structural similarity, followed by visual inspection. This revealed a group of highly related compounds resembling the natural alkaloid staurosporine (Fig 1A). Staurosporine and many of its derivatives are potent broad-spectrum kinase inhibitors and have been investigated for the treatment of a variety of diseases, including cancer. One such derivative, PKC412 (midostaurin), has advanced into phase III clinical trials for the treatment of acute myeloid leukemia (AML) expressing the mutant tyrosine kinase receptor FLT3/CD135, itself a PKC412 target (Fischer et al, 2010). Like staurosporine, PKC412 is a multi-target protein kinase inhibitor and has been shown to have low nanomolar activity against additional kinases including c-KIT, PDGFR and several PKC family members.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

No MeSH data available.


Related in: MedlinePlus