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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

Chemical proteomics and computational modeling highlight SYK as a candidate critical node in basal-like breast cancer cellsA A panel of four basal-like and three luminal breast cancer cell lines were treated with the indicated inhibitors targeting canonical PKC412 targets. Red color shading indicates EC50. Grayed out boxes indicate cell line/drug combinations that were not tested.B Immobilized PKC412 was used to identify binders in MDA-MB-468 cell lysates by mass spectrometry. Specific and non-specific binders were identified by competition with free PKC412 or the structurally similar but unspecific compound LY333531, respectively. Specific PKC412 binders were mapped onto the kinase tree (solid red circles).C Venn diagram showing genes differentially expressed (> threefold) upon PKC412 (500 nM) treatment for 6 h in basal-like (MDA-MB-468, red) and luminal (ZR75-1, blue) breast cancer cell lines.D Most significantly perturbed protein–protein interaction subnetwork (P < 0.005) upon PKC412 treatment. Red lines indicate direct interactions with a PKC412 target. Blue lines indicate indirect interactions. Edge thickness indicates simultaneous regulation upon PKC412 treatment (see Materials and Methods).E Heatmap showing the impact of the individual PKC412 targets on selected GO terms (see also Supplementary Table S3). Red represents reduced association with the GO term, therefore indicating potentially essential targets. Blue represents dispensable targets.
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fig03: Chemical proteomics and computational modeling highlight SYK as a candidate critical node in basal-like breast cancer cellsA A panel of four basal-like and three luminal breast cancer cell lines were treated with the indicated inhibitors targeting canonical PKC412 targets. Red color shading indicates EC50. Grayed out boxes indicate cell line/drug combinations that were not tested.B Immobilized PKC412 was used to identify binders in MDA-MB-468 cell lysates by mass spectrometry. Specific and non-specific binders were identified by competition with free PKC412 or the structurally similar but unspecific compound LY333531, respectively. Specific PKC412 binders were mapped onto the kinase tree (solid red circles).C Venn diagram showing genes differentially expressed (> threefold) upon PKC412 (500 nM) treatment for 6 h in basal-like (MDA-MB-468, red) and luminal (ZR75-1, blue) breast cancer cell lines.D Most significantly perturbed protein–protein interaction subnetwork (P < 0.005) upon PKC412 treatment. Red lines indicate direct interactions with a PKC412 target. Blue lines indicate indirect interactions. Edge thickness indicates simultaneous regulation upon PKC412 treatment (see Materials and Methods).E Heatmap showing the impact of the individual PKC412 targets on selected GO terms (see also Supplementary Table S3). Red represents reduced association with the GO term, therefore indicating potentially essential targets. Blue represents dispensable targets.

Mentions: PKC412 has been shown to be a potent inhibitor of several kinases, including FLT3, c-KIT, VEGFR and several PKC family members. Therefore, we investigated whether six structurally unrelated compounds that inhibit various combinations of these ‘canonical’ targets could specifically induce cell death in the basal-like breast cancer cell lines. Only the PKC412 structural analog Go6976 recapitulated the profile, suggesting that a non-canonical target may be responsible for, or at least contribute to, the specificity for TNBC cells (Fig 3A, Supplementary Fig S3 and Supplementary Dataset S2). Of note, the PKC inhibitor LY333531, a compound structurally related to PKC412, did not display the PKC412 cell line specificity pattern, indicating that this small molecule does not inhibit the critical PKC412 target(s) (Fig 3A, Supplementary Fig S4).


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)

Chemical proteomics and computational modeling highlight SYK as a candidate critical node in basal-like breast cancer cellsA A panel of four basal-like and three luminal breast cancer cell lines were treated with the indicated inhibitors targeting canonical PKC412 targets. Red color shading indicates EC50. Grayed out boxes indicate cell line/drug combinations that were not tested.B Immobilized PKC412 was used to identify binders in MDA-MB-468 cell lysates by mass spectrometry. Specific and non-specific binders were identified by competition with free PKC412 or the structurally similar but unspecific compound LY333531, respectively. Specific PKC412 binders were mapped onto the kinase tree (solid red circles).C Venn diagram showing genes differentially expressed (> threefold) upon PKC412 (500 nM) treatment for 6 h in basal-like (MDA-MB-468, red) and luminal (ZR75-1, blue) breast cancer cell lines.D Most significantly perturbed protein–protein interaction subnetwork (P < 0.005) upon PKC412 treatment. Red lines indicate direct interactions with a PKC412 target. Blue lines indicate indirect interactions. Edge thickness indicates simultaneous regulation upon PKC412 treatment (see Materials and Methods).E Heatmap showing the impact of the individual PKC412 targets on selected GO terms (see also Supplementary Table S3). Red represents reduced association with the GO term, therefore indicating potentially essential targets. Blue represents dispensable targets.
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig03: Chemical proteomics and computational modeling highlight SYK as a candidate critical node in basal-like breast cancer cellsA A panel of four basal-like and three luminal breast cancer cell lines were treated with the indicated inhibitors targeting canonical PKC412 targets. Red color shading indicates EC50. Grayed out boxes indicate cell line/drug combinations that were not tested.B Immobilized PKC412 was used to identify binders in MDA-MB-468 cell lysates by mass spectrometry. Specific and non-specific binders were identified by competition with free PKC412 or the structurally similar but unspecific compound LY333531, respectively. Specific PKC412 binders were mapped onto the kinase tree (solid red circles).C Venn diagram showing genes differentially expressed (> threefold) upon PKC412 (500 nM) treatment for 6 h in basal-like (MDA-MB-468, red) and luminal (ZR75-1, blue) breast cancer cell lines.D Most significantly perturbed protein–protein interaction subnetwork (P < 0.005) upon PKC412 treatment. Red lines indicate direct interactions with a PKC412 target. Blue lines indicate indirect interactions. Edge thickness indicates simultaneous regulation upon PKC412 treatment (see Materials and Methods).E Heatmap showing the impact of the individual PKC412 targets on selected GO terms (see also Supplementary Table S3). Red represents reduced association with the GO term, therefore indicating potentially essential targets. Blue represents dispensable targets.
Mentions: PKC412 has been shown to be a potent inhibitor of several kinases, including FLT3, c-KIT, VEGFR and several PKC family members. Therefore, we investigated whether six structurally unrelated compounds that inhibit various combinations of these ‘canonical’ targets could specifically induce cell death in the basal-like breast cancer cell lines. Only the PKC412 structural analog Go6976 recapitulated the profile, suggesting that a non-canonical target may be responsible for, or at least contribute to, the specificity for TNBC cells (Fig 3A, Supplementary Fig S3 and Supplementary Dataset S2). Of note, the PKC inhibitor LY333531, a compound structurally related to PKC412, did not display the PKC412 cell line specificity pattern, indicating that this small molecule does not inhibit the critical PKC412 target(s) (Fig 3A, Supplementary Fig S4).

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