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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

PKC412 targets basal-like breast cancer cells in vitro and in vivoA Panel of 28 breast cancer cell lines treated with increasing doses (Log2) PKC412 for 5 days. The column after the cell line name indicates intrinsic subtype (blue, luminal; red, basal).B PKC412 dose–response curve for a low passage patient-derived TNBC cell line (PDC44) and a luminal control cell line (ZR75-1).C Apoptosis as determined by annexin V staining in basal (red) and luminal (blue) cells treated with PKC412 (500 nM, 16 h) or camptothecin (CPT). ***P < 0.001, ns = not significant. n = 3. Statistical significance was analyzed by ANOVA.D Xenograft model of Cal51 basal breast cancer cells treated with PKC412 for 35 days (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 Akaike information criterion (AIC). n ≥ 3.E Patient-derived xenograft (PDX137) model of a triple-negative breast cancer patient treated with PKC412 (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 (AIC). n ≥ 3.
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fig02: PKC412 targets basal-like breast cancer cells in vitro and in vivoA Panel of 28 breast cancer cell lines treated with increasing doses (Log2) PKC412 for 5 days. The column after the cell line name indicates intrinsic subtype (blue, luminal; red, basal).B PKC412 dose–response curve for a low passage patient-derived TNBC cell line (PDC44) and a luminal control cell line (ZR75-1).C Apoptosis as determined by annexin V staining in basal (red) and luminal (blue) cells treated with PKC412 (500 nM, 16 h) or camptothecin (CPT). ***P < 0.001, ns = not significant. n = 3. Statistical significance was analyzed by ANOVA.D Xenograft model of Cal51 basal breast cancer cells treated with PKC412 for 35 days (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 Akaike information criterion (AIC). n ≥ 3.E Patient-derived xenograft (PDX137) model of a triple-negative breast cancer patient treated with PKC412 (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 (AIC). n ≥ 3.

Mentions: Next, we tested PKC412 cytotoxicity on a panel of 28 breast cancer cell lines representing the major intrinsic subtypes (Neve et al, 2006). As basal-like tumors are enriched for mesenchymal features and cell lines have been grouped according to the intrinsic classification, we focused on basal-like and luminal cell lines (Perou et al, 2000; Neve et al, 2006; Prat et al, 2010). Sensitivity varied dramatically across the cell line panel (Fig 2A, Supplementary Dataset S1): Several cell lines were refractory to PKC412 even at the highest concentration tested (50 μM), whereas others were strongly inhibited.


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)

PKC412 targets basal-like breast cancer cells in vitro and in vivoA Panel of 28 breast cancer cell lines treated with increasing doses (Log2) PKC412 for 5 days. The column after the cell line name indicates intrinsic subtype (blue, luminal; red, basal).B PKC412 dose–response curve for a low passage patient-derived TNBC cell line (PDC44) and a luminal control cell line (ZR75-1).C Apoptosis as determined by annexin V staining in basal (red) and luminal (blue) cells treated with PKC412 (500 nM, 16 h) or camptothecin (CPT). ***P < 0.001, ns = not significant. n = 3. Statistical significance was analyzed by ANOVA.D Xenograft model of Cal51 basal breast cancer cells treated with PKC412 for 35 days (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 Akaike information criterion (AIC). n ≥ 3.E Patient-derived xenograft (PDX137) model of a triple-negative breast cancer patient treated with PKC412 (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 (AIC). n ≥ 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig02: PKC412 targets basal-like breast cancer cells in vitro and in vivoA Panel of 28 breast cancer cell lines treated with increasing doses (Log2) PKC412 for 5 days. The column after the cell line name indicates intrinsic subtype (blue, luminal; red, basal).B PKC412 dose–response curve for a low passage patient-derived TNBC cell line (PDC44) and a luminal control cell line (ZR75-1).C Apoptosis as determined by annexin V staining in basal (red) and luminal (blue) cells treated with PKC412 (500 nM, 16 h) or camptothecin (CPT). ***P < 0.001, ns = not significant. n = 3. Statistical significance was analyzed by ANOVA.D Xenograft model of Cal51 basal breast cancer cells treated with PKC412 for 35 days (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 Akaike information criterion (AIC). n ≥ 3.E Patient-derived xenograft (PDX137) model of a triple-negative breast cancer patient treated with PKC412 (oral 100 mg/kg, daily). Shown are the mean and SEM. P < 0.01 (AIC). n ≥ 3.
Mentions: Next, we tested PKC412 cytotoxicity on a panel of 28 breast cancer cell lines representing the major intrinsic subtypes (Neve et al, 2006). As basal-like tumors are enriched for mesenchymal features and cell lines have been grouped according to the intrinsic classification, we focused on basal-like and luminal cell lines (Perou et al, 2000; Neve et al, 2006; Prat et al, 2010). Sensitivity varied dramatically across the cell line panel (Fig 2A, Supplementary Dataset S1): Several cell lines were refractory to PKC412 even at the highest concentration tested (50 μM), whereas others were strongly inhibited.

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