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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

SYK kinase activity is specifically required in basal-like breast cancer cell linesA Cell line panel of basal-like (n = 9) and luminal cells (n = 10) treated with two SYK inhibitors. P < 0.0001 for R406 and P < 0.01 for BAY61-6306, Mann–Whitney U-test.B Dose–response experiment with the SYK inhibitor BAY61-3606 on TGF-β- or vehicle-treated MMEC-HRASV12G cells. Data are expressed as mean ± SD, n = 3.C Cells as in (B) treated with the SYK inhibitor R406. Data are expressed as mean ± SD, n = 3.D MDA-MB-468 transfected with a SYK cDNA or GFP-expressing vector were treated with 10 μM BAY61-3606 for 7 days. Cells were visualized using crystal violet.
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fig05: SYK kinase activity is specifically required in basal-like breast cancer cell linesA Cell line panel of basal-like (n = 9) and luminal cells (n = 10) treated with two SYK inhibitors. P < 0.0001 for R406 and P < 0.01 for BAY61-6306, Mann–Whitney U-test.B Dose–response experiment with the SYK inhibitor BAY61-3606 on TGF-β- or vehicle-treated MMEC-HRASV12G cells. Data are expressed as mean ± SD, n = 3.C Cells as in (B) treated with the SYK inhibitor R406. Data are expressed as mean ± SD, n = 3.D MDA-MB-468 transfected with a SYK cDNA or GFP-expressing vector were treated with 10 μM BAY61-3606 for 7 days. Cells were visualized using crystal violet.

Mentions: R406 and BAY61-3606, two structurally unrelated and selective small-molecule inhibitors of SYK, were also specifically cytotoxic for basal-like cell lines (Fig 5A). These compounds were also more potent in killing the MMEC cells that had undergone EMT induced by TGF-β (Fig 5B and C). Ectopic overexpression of SYK in MDA-MB-468 cells and HCC70 cells partially rescued SYK inhibitor (BAY61-3606) cytotoxicity, which is consistent with the notion that this compound induces toxicity through the inhibition of SYK kinase activity (Fig 5D and Supplementary Figs S14 and S15). Thus, the inhibition of SYK explains at least part of the basal-like TBNC cell line specificity profile of PKC412. Importantly, these experiments reveal the non-oncogene addiction of a subset of breast cancer cell lines to SYK and thereby identify SYK as a novel and critical breast cancer target.


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)

SYK kinase activity is specifically required in basal-like breast cancer cell linesA Cell line panel of basal-like (n = 9) and luminal cells (n = 10) treated with two SYK inhibitors. P < 0.0001 for R406 and P < 0.01 for BAY61-6306, Mann–Whitney U-test.B Dose–response experiment with the SYK inhibitor BAY61-3606 on TGF-β- or vehicle-treated MMEC-HRASV12G cells. Data are expressed as mean ± SD, n = 3.C Cells as in (B) treated with the SYK inhibitor R406. Data are expressed as mean ± SD, n = 3.D MDA-MB-468 transfected with a SYK cDNA or GFP-expressing vector were treated with 10 μM BAY61-3606 for 7 days. Cells were visualized using crystal violet.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4358660&req=5

fig05: SYK kinase activity is specifically required in basal-like breast cancer cell linesA Cell line panel of basal-like (n = 9) and luminal cells (n = 10) treated with two SYK inhibitors. P < 0.0001 for R406 and P < 0.01 for BAY61-6306, Mann–Whitney U-test.B Dose–response experiment with the SYK inhibitor BAY61-3606 on TGF-β- or vehicle-treated MMEC-HRASV12G cells. Data are expressed as mean ± SD, n = 3.C Cells as in (B) treated with the SYK inhibitor R406. Data are expressed as mean ± SD, n = 3.D MDA-MB-468 transfected with a SYK cDNA or GFP-expressing vector were treated with 10 μM BAY61-3606 for 7 days. Cells were visualized using crystal violet.
Mentions: R406 and BAY61-3606, two structurally unrelated and selective small-molecule inhibitors of SYK, were also specifically cytotoxic for basal-like cell lines (Fig 5A). These compounds were also more potent in killing the MMEC cells that had undergone EMT induced by TGF-β (Fig 5B and C). Ectopic overexpression of SYK in MDA-MB-468 cells and HCC70 cells partially rescued SYK inhibitor (BAY61-3606) cytotoxicity, which is consistent with the notion that this compound induces toxicity through the inhibition of SYK kinase activity (Fig 5D and Supplementary Figs S14 and S15). Thus, the inhibition of SYK explains at least part of the basal-like TBNC cell line specificity profile of PKC412. Importantly, these experiments reveal the non-oncogene addiction of a subset of breast cancer cell lines to SYK and thereby identify SYK as a novel and critical breast cancer target.

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