Ontology highlight
ABSTRACT:
PROVIDER: PRJNA381624 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5413470.fastq.gz | Fastqsanger.gz | |||
| SRR5413480.fastq.gz | Fastqsanger.gz | |||
| SRR5413490.fastq.gz | Fastqsanger.gz | |||
| SRR5413500.fastq.gz | Fastqsanger.gz | |||
| SRR5413510.fastq.gz | Fastqsanger.gz |
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Project description:Recent studies reveal that a subset of cancers in various indications are dependent on high and constant expression of certain transcription factors for growth and survival, a phenomenon termed as transcriptional addiction. Therefore, targeting transcriptional machinery can potentially lead to potent and selective anticancer effects. CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Its function is required for both cell cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive target in cancer since its inhibition leads to decrease of the transcript levels of oncogenic transcription factors, especially those associated with super-enhancers (SEs). Here we describe a first-in-class CDK7 inhibitor SY-1365, which covalently targets a cysteine outside the kinase domain, resulting in sustained, highly selective inhibition of CDK7. In vitro studies reveal that SY-1365 has potency in a wide range of cancer models with low micromolar IC50 values. Cancer cells with low BCL-XL expression are found to be more dependent on MCL1 for survival and therefore particularly sensitive towards SY-1365 treatment since SY-1365 downregulates MCL1 protein level. SY-1365 treatment induces distinct transcriptional changes in acute myeloid leukemia (AML) cell lines. SY-1365 also demonstrates substantial anti-tumor effects in multiple AML xenograft models. Additionally, combination treatment with venetoclax shows synergistic effects in AML models both in vitro and in vivo. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. SY-1365 is currently being assessed in a Phase I trial in adult patients (NCT03134638) We performed microarray based expression profiling to quantify transcriptional changes upon treatment with the CDK7 inhibitor, SY-1365 and to compare it to transcriptional changes induced by treatment with other transcriptional drugs JQ1 (BRD4 inhibitor), NVP2 (CDK9 inhibitor) and flavopiridol (pan-CDK inhibitor). We profiled a human acute myeloid leukemia (AML) cell line THP-1. Cells were treated with either DMSO, 100nm SY-1365, 25nM NVP2 , 250nM JQ1 or 200nM flavopiridol for two and six hours. All samples were prepared in biological triplicate.
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Project description:Recent studies reveal that a subset of cancers in various indications are dependent on high and constant expression of certain transcription factors for growth and survival, a phenomenon termed as transcriptional addiction. Therefore, targeting transcriptional machinery can potentially lead to potent and selective anticancer effects. CDK7 is the catalytic subunit of the CDK-activating kinase (CAK) complex. Its function is required for both cell cycle regulation and transcriptional control of gene expression. CDK7 has recently emerged as an attractive target in cancer since its inhibition leads to decrease of the transcript levels of oncogenic transcription factors, especially those associated with super-enhancers (SEs). Here we describe a first-in-class CDK7 inhibitor SY-1365, which covalently targets a cysteine outside the kinase domain, resulting in sustained, highly selective inhibition of CDK7. In vitro studies reveal that SY-1365 has potency in a wide range of cancer models with low micromolar IC50 values. Cancer cells with low BCL-XL expression are found to be more dependent on MCL1 for survival and therefore particularly sensitive towards SY-1365 treatment since SY-1365 downregulates MCL1 protein level. SY-1365 treatment induces distinct transcriptional changes in acute myeloid leukemia (AML) cell lines. SY-1365 also demonstrates substantial anti-tumor effects in multiple AML xenograft models. Additionally, combination treatment with venetoclax shows synergistic effects in AML models both in vitro and in vivo. Our findings support targeting CDK7 as a new approach for treating transcriptionally addicted cancers. SY-1365 is currently being assessed in a Phase I trial in adult patients (NCT03134638)
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Project description:Rising blast-percentage or secondary (s) AML transformation (sAML) in MPNs leads to JAK inhibitor (JAKi) therapy-resistance and poor survival. Here, we demonstrate that the CDK7 inhibitor (CDK7i) SY-5609 treatment depletes phenotypically-characterized post-MPN-sAML stem/progenitor cells. In the cultured post-MPN sAML SET2 and HEL as well as patient-derived (PD) post-MPN-sAML cells, SY-5609 treatment inhibited growth and induced lethality, while sparing normal cells. RNA-Seq analysis following SY-5609 treatment demonstrated reduced mRNA expressions of MYC, MYB, CDK4/6, PIM1, and CCND1, but increased mRNA levels of CDKN1A and BCL2L1. Mass spectrometry of SY-5609-treated MPN-sAML cells also demonstrated reduced c-Myc, c-Myb, PIM1, and CDK4/6 but increased p21, caspase 9 and BAD protein levels. CRISPR-mediated CDK7 depletion also reduced viability of HEL cells. CyTOF analysis of SY-5609-treated PD, post-MPN-sAML stem/progenitor cells showed reduced c-Myc, CDK6 and PU.1, but increased protein levels of CD11b, p21 and cleaved Caspase 3. Co-treatment with SY-5609 and ruxolitinib was synergistically lethal in HEL, SET2 and PD post-MPN-sAML cells. A CRISPR screen in SET2 and HEL cells revealed BRD4, CBP and p300 as co-dependencies with SY-5609 treatment. Accordingly, co-treatment with SY-5609 and the BETi OTX015 or pelabresib or with the CBP/p300 inhibitor GNE-049 was synergistically lethal in MPN-sAML cells (including those exhibiting TP53 loss). Finally, in the HEL-Luc/GFP xenograft model, compared to each agent alone, co-treatment with SY-5609 and OTX015 reduced post-MPN-sAML burden and improved survival without inducing host toxicity. These findings demonstrate promising preclinical activity of the CDK7i-based combinations with BETi or HATi against advanced-MPNs, including post-MPN-sAML.
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