Immobilized metal ion affinity chromatography Phosphopeptides were enriched by

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 Immobilized metal ion affinity chromatography Phosphopeptides were enriched by  Empty Immobilized metal ion affinity chromatography Phosphopeptides were enriched by

Post  jy9202 on Wed Feb 12, 2014 6:58 am

PCA and unsuper vised hierarchical clustering analysis classified cell lines according to their pathology, thus indicating that the phosphopro teomes of cells of the same pathology are more similar than those derived from Amuvatinib 構造 different diseases. Furthermore, PC1 in the PCA and unsupervised hierarchical cluster ing clearly separated AML cells that have a myeloid lineage from the other two diseases that have a lymphoid lineage.

We evaluated the potential ability of phosphoproteo mics data in predicting drug response through a robust cross validation framework based on Lasso regression analysis, showing that the phosphorylation levels of a AT-406 生産者 relatively small subset of phosphopeptides was informa tive with regard to treatment outcomes, In addition, using a complementary approach based on a correlation study, we identified phosphopeptide sets whose combined intensities correlated with the responses to the three compounds with remarkable correlation coefficients, In addition to observing strong correlations with cell viability, we also found that the magnitude of changes between the phos phopeptide signatures of the most resistant and most sensitive cells were greater, or close, to 100 fold in each case, These large differences in phosphopeptide intensities are noteworthy and important as ideal predictors of response need to show robust dif ferences and steep slopes in the regression function in addition to having a good correlation. Therefore, our proof of concept study indicates that phosphoproteomics may represent a general tool to identify biomarkers of response to kinase inhibitors and to classify cancers based on their likelihood that these respond to targeted therapies.

Although some peptides that predicted responses to kinase inhibitors in AML were also asso ciated with responses to the same inhibitors in lym phoma and multiple myeloma cells, there were subsets of phosphopeptides that predicted responses AG-490 構造 in AML cells only. This could be attributed to the marked differences in the patterns of basal phosphorylation between lymphoma, multiple myeloma, and AML cells which may be a reflection of differences in the activity of kinase signaling across these diseases.

The correlation between PI3K pathway activity markers and sensitivity to PI3K compounds has been found to be weak in recent studies, For example, no correlation between activating mutations on PIK3CA with responses to PI3K inhibitors were found in cell lines, while a recently reported clinical trial found that just 30% of breast and gynecologic patients harboring PIK3CA mutations responded to PI3K therapies, Dan et al. found a weak correlation between responses to PI3K inhibitors and phosphorylation of Akt, which is a marker of PI3K activity. Although the primary aim of this work was not to identify mechanisms of resis tance, it was interesting to observe that, consistent with the data in Dan et al. and Alcolea et al.


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