Targeting PBK/TOPK decreases growth and survival of glioblastoma stem cells in vitro and attenuates tumor growth in vivo
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE53800 | GEO | 2015/06/16
SECONDARY ACCESSION(S): PRJNA233313
REPOSITORIES: GEO
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Project description:Breast cancer stem cells (BCSCs) are responsible for tumor recurrence and therapy resistance. We have established primary BCSC cultures from human tumors of triple-negative breast cancer (TNBC), a subgroup of breast cancer likely driven by BCSCs. Primary BCSCs generate xenografts phenocopying the tumors of origin, representing a suitable model to investigate breast cancer targeting strategies. In the TNBC cell line MDA-MB-468, we previously screened kinases whose depletion elicited a differentiation response, among which IRAK2 was identified. Since IRAK2 is highly enriched in primary BCSCs we wondered if its depletion could affect their growth. Primary BCSCs and MDA-MB-468 presenting IRAK2 downregulation exhibited decreased proliferation and sphere-forming capacity, evidencing the role of IRAK2 in cellular growth and self-renewal. When transplanted orthotopically into immunocompromised mice, IRAK2 knockdown cells originated smaller xenografts in comparison with control cells, suggesting that IRAK2 downregulation may delay tumor development. Investigating the molecular pathways affected by the knockdown, NF-κB and ERK phosphorylation, IL-6 and cyclin D1 expression, ERN1 signaling and autophagy were decreased in a cell line-dependent way. Transcriptome analysis confirmed that the cells were to some extent differently affected by the knockdown, indicating that their heterogeneity, different mutations, genetic background, expression of IRAK2 and level of its downregulation could influence the outcome of the knockdown. Given that overall IRAK2 downregulation decreased cellular ability to sustain aggressive growth and to endure cellular stress, IRAK2 may be considered an interesting target to compromise TNBC progression, positively contributing to TNBC clinical outcome.
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Project description:Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has long been considered a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. However, despite promising early clinical data in blood cancers using pan-CDK inhibitors that potently inhibit CDK9 such as Dinaciclib and Flavopiridol, no selective CDK9 inhibitors have been clinically approved. Here we show that a multi-targeted CDK inhibitor can be used to develop a selective CDK9 degrader exemplified by THAL-SNS-032, a hetero-bifunctional molecule composed of SNS-032, a CDK2,7,9 inhibitor conjugated to thalidomide, a small molecule binder of Cereblon. We demonstrate that THAL-SNS-032 can recruit the E3 ubiquitin ligase Cereblon to CDK9 and induce its proteasome-mediated degradation. Treatment of cells with low nanomolar concentrations of THAL-SNS-032 resulted in rapid and efficient CDK9 degradation but did not affect levels of other SNS-032 targets, including CDK2 and CDK7. Consistent with this selective degradation phenotype, transcriptional profiling of THAL-SNS-032 indicated that its transcriptional effects were more similar to that of a selective CDK9 inhibitor, NVP2, than that of the nonselective SNS-032 parent compound. Moreover, THAL-SNS-032, in contrast to traditional CDK9 inhibitors, retained potent pro-apoptotic activity even after compound removal from cells. This suggests that degradation of CDK9 leads to prolonged cytotoxic effects as compared to CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation may be a promising strategy for converting multi-targeting inhibitors into selective degraders, and that the pharmacological effects of kinase degradation can be distinct from kinase inhibition.
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Project description:Cyclin dependent kinase 9 (CDK9), a key regulator of transcriptional elongation, has long been considered a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. However, despite promising early clinical data in blood cancers using pan-CDK inhibitors that potently inhibit CDK9 such as Dinaciclib and Flavopiridol, no selective CDK9 inhibitors have been clinically approved. Here we show that a multi-targeted CDK inhibitor can be used to develop a selective CDK9 degrader exemplified by THAL-SNS-032, a hetero-bifunctional molecule composed of SNS-032, a CDK2,7,9 inhibitor conjugated to thalidomide, a small molecule binder of Cereblon. We demonstrate that THAL-SNS-032 can recruit the E3 ubiquitin ligase Cereblon to CDK9 and induce its proteasome-mediated degradation. Treatment of cells with low nanomolar concentrations of THAL-SNS-032 resulted in rapid and efficient CDK9 degradation but did not affect levels of other SNS-032 targets, including CDK2 and CDK7. Consistent with this selective degradation phenotype, transcriptional profiling of THAL-SNS-032 indicated that its transcriptional effects were more similar to that of a selective CDK9 inhibitor, NVP2, than that of the nonselective SNS-032 parent compound. Moreover, THAL-SNS-032, in contrast to traditional CDK9 inhibitors, retained potent pro-apoptotic activity even after compound removal from cells. This suggests that degradation of CDK9 leads to prolonged cytotoxic effects as compared to CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation may be a promising strategy for converting multi-targeting inhibitors into selective degraders, and that the pharmacological effects of kinase degradation can be distinct from kinase inhibition.
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