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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [ChIP-Seq]

ABSTRACT: More than 500 kinases are implicated in the control of virtually every cellular process in mammals and deregulation of their activity is causally linked to diseases ranging from cancer to inflammatory and degenerative disorders. In the last three decades, massive worldwide efforts led to the approval of 62 clinical kinase inhibitors (CKI), with hundreds of additional molecules in various stages of pre-clinical or clinical development. In addition to the intended target(s), small molecule CKI commonly inhibit multiple additional kinases, resulting in both enhanced clinical effects and undesired side effects that are largely unpredictable based on in vitro selectivity profiling. To complement current CKI profiling methods, we set out a novel experimental and analytical approach grounded on the use of chromatin modifications as unbiased and information-rich readouts of the functional effects of CKI on macrophage activation, a complex biological response of biomedical relevance. This approach allowed us to characterize and dissect the distinctive behaviors of CKI with identical intended targets as well as to discover undescribed activities of CKI on macrophage activation programs.

ORGANISM(S): Mus musculus

PROVIDER: GSE219239 | GEO | 2024/04/16

REPOSITORIES: GEO

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [RNA-Seq]

Project description:More than 500 kinases are implicated in the control of virtually every cellular process in mammals and deregulation of their activity is causally linked to diseases ranging from cancer to inflammatory and degenerative disorders. In the last three decades, massive worldwide efforts led to the approval of 62 clinical kinase inhibitors (CKI), with hundreds of additional molecules in various stages of pre-clinical or clinical development. In addition to the intended target(s), small molecule CKI commonly inhibit multiple additional kinases, resulting in both enhanced clinical effects and undesired side effects that are largely unpredictable based on in vitro selectivity profiling. To complement current CKI profiling methods, we set out a novel experimental and analytical approach grounded on the use of chromatin modifications as unbiased and information-rich readouts of the functional effects of CKI on macrophage activation, a complex biological response of biomedical relevance. This approach allowed us to characterize and dissect the distinctive behaviors of CKI with identical intended targets as well as to discover undescribed activities of CKI on macrophage activation programs.

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A phosphatase-like nanomaterial promotes autophagy and reprograms macrophage for cancer immunotherapy

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Project description:We have used computational and experimental biology approaches to identify candidate mechanisms of action of a traditional Chinese medicine; Compound Kushen Injection (CKI), in a breast cancer cell line in which CKI has been shown to cause apoptosis. Because CKI is a complex mixture of plant secondary metabolites, we used a high-performance liquid chromatography (HPLC) fractionation and reconstitution approach to define chemical fractions required for CKI to induce apoptosis in MDA-MB-231 cells. Our initial fractionation separated major from minor compounds, and showed that the major compounds accounted for little of the activity of CKI. By systematically perturbing the major compounds in CKI we found that removal of no single major compound could alter the effect of CKI on cell viability and apoptosis. However, simultaneous removal of two major compounds identified oxymatrine and oxysophocarpine as critical compounds with respect to CKI activity. We then used RNA sequencing and transcriptome analysis to correlate compound removal with gene expression and phenotype data. We determined that many compounds in CKI are required for its effectiveness in triggering apoptosis but that significant modulation of its activity is conferred by a small number of compounds. In conclusion, CKI may be typical of many plant based extracts that contain many compounds in that no single compound is responsible for all of the bioactivity of the mixture and that many compounds interact in a complex fashion to influence a network containing many targets.

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