Combining CDK12 and BAF inhibition synergistically impairs cancer cell survival in triple-negative breast cancer line
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE311170 | GEO | 2025/11/25
REPOSITORIES: GEO
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Project description:Combining CDK12 and BAF inhibition synergistically impairs cancer cell survival in triple-negative breast cancer line
| PRJNA1368744 | ENA
Project description:We demonstrate that the loss of CDK12 protein or activity, unlike CDK9 or CDK7, significantly upregulates the expression of certain genes, including genes whose activation contributes to the anti-proliferative effects of CDK12 inhibition. In HER2+ breast cancer, a malignancy where CDK12 is almost invariably co-amplified with HER2, CDK12 inhibition drives up the expression of MYC, which is toxic to HER2+ cancer cells. This upregulation of c-myc largely mediates the killing effect of CDK12 inhibition. Therefore, we report a novel mode of regulation of gene expression via CDK12, which represents a promising target for cancer driven by HER2 gene amplification.
2024-02-12 | GSE181905 | GEO
Project description:The cyclin-dependent kinase CDK12 promotes transcription completion of long genes by suppressing the utilization of intronic polyadenylation sites that cause premature transcriptional termination. One class of genes that are particularly affected by loss of CDK12 activity are DNA damage response genes and therefore inhibitors of CDK12 have garnered interest as cancer therapeutic amplifiers. In this study, we used the CDK12/13 inhibitor THZ531 to treat HF1 (normal human fibroblasts), K562 and HeLa cells and the adenine analog 1-NM-PP1 to treat analog-sensitive HeLa cells and to assess the acute effects on transcription and RNA processing using Bru-seq and BruChase-seq. While acute transcriptional changes were small and limited to the 3’-ends of genes, RNA turnover was dramatically affected by CDK12 inhibition. Importantly, the downregulation of DNA damage response genes was predominantly due to increased mRNA turnover. Co-transcriptional splicing was suppressed by CDK12 inhibition. Finally, many introns that showed premature transcriptional termination were found to be resistant to degradation following CDK12 inhibition despite showing efficient splicing. We speculate that premature termination and addition of poly(A)s protect these spliced intronic fragments from degradation. These studies reveal previously unknown roles of CDK12 in regulating RNA turnover and co-transcriptional splicing.
2022-09-17 | GSE191222 | GEO
Project description:We describe the epigenetic profiling of the H3K9me2 and HP1a in Drosophila third instar larvae before and after CDK12 depletion by RNA interference (RNAi). Here we show that CDK12 regulates heterochromatin dynamics in Drosophila chromosomes. Depletion of CDK12 induces the increased HP1a and H3K9me2 binding profile on the coding region of euchromatic genes, with the X chromosome being the most affected. These results are consistent with the polytene chromosome immunostaining pattern of HP1a and H3K9me2 after CDK12 knockdown in our initial cytological observations, which show that CDK12 depletion induce heterochromatin spreading on euchromatic arms, especially on the X chromosome. This study describes a novel role of the CDK12 complex in controlling the epigenetic transition between euchromatin and heterochromatin. Examination of the genome-wide H3K9me2 and HP1a binding profile in wildtype larvae (WT) and CDK12-depleted larvae (CDK12-KD). Examination of the genome-wide CDK12 binding profile in wildtype larvae (WT). Twelve independent immunoprecipitations were conducted for each antibody. Two biological replicates were performed.
2015-11-02 | E-GEOD-63011 | biostudies-arrayexpress
Project description:P-TEFb and CDK12 facilitate transcription elongation by RNA polymerase II and play prominent roles in cancer. Understanding their functional interplay could inform novel anti-cancer strategies. While inhibition of CDK12 downregulates unique sets of genes, eliciting genomic instability that is being exploited for novel therapies, little is known about the significance of transcriptional induction in CDK12-targeted cells. We show that inhibition of CDK12 in colon cancer-derived cells activates P-TEFb and induces genes of key cancer signaling pathways, including p53 and NF-kB. Mechanistically, cancer cells become exquisitely dependent on P-TEFb through activation of p53-dependent apoptosis and attenuation of NF-kB-dependent proliferation. Furthermore, we show that the DNA damage-responsive ATM kinase mediates these effects. While ATM is required for the synthetic lethality of CDK12 and P-TEFb co-targeting in p53-proficient cells, co-inhibition of ATM and CDK12 synergizes in decreasing viability of p53-deficient cells. Finally, pairwise targeting of CDK12, P-TEFb and transcription initiation kinase CDK7 stimulates p53-dependent apoptosis of cancer cell spheroids. We propose that the stimulation of Pol II pause release by P-TEFb at the signal-responsive genes underlies the dependence of CDK12-targeted cancer cells on P-TEFb. Together, our work provides a rationale for combinatorial targeting of CDK12 and P-TEFb or the induced oncogenic pathways in cancer.
2023-09-17 | GSE236803 | GEO
Project description:In a forward genetic screen, we have previously identified a null mutant of Cdk12 that results in alterations in actin dynamics, the axon initial segment and electrophysiology in Drosophila melanogaster. To decipher how Cdk12 may be having these effects, we extracted RNA from pooled Drosophila heads and compared Cdk12-null mutants to controls at the transcriptome level.
2023-01-01 | E-MTAB-12090 | biostudies-arrayexpress
Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.
2016-08-29 | GSE72022 | GEO
Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.
2016-05-19 | GSE72023 | GEO
Project description:Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the study of prostate cancer. Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC.
2024-04-17 | GSE254388 | GEO
Project description:Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a unique molecular subtype of metastatic castration resistant prostate cancer (mCRPC). It remains unclear, however, whether CDK12 loss per se is sufficient to drive prostate cancer development—either alone, or in the context of other genetic alterations—and whether CDK12-mutant tumors exhibit sensitivity to specific pharmacotherapies. Here, we demonstrate that tissue-specific Cdk12 ablation is sufficient to induce preneoplastic lesions in the mouse prostate. Allograft-based CRISPR screening demonstrated that Cdk12 loss is positively associated with p53 inactivation, but negatively associated with Pten inactivation—similar to what is seen in human mCRPC. Consistent with this, ablation of Cdk12 in prostate organoids with concurrent p53 loss promotes their proliferation and ability to form tumors in mice, while Cdk12 knockout in the Pten-null prostate cancer mouse model abrogates tumor growth. Bigenic CDK12 and p53 loss allografts represent a new syngeneic model for the study of prostate cancer. Cdk12-null organoids (either with or without p53 co-ablation) and patient-derived xenografts from tumors with CDK12 inactivation are highly sensitive to inhibition or degradation of its paralog kinase, CDK13. Together, these data identify CDK12 as a bona fide tumor suppressor gene with impact on tumor progression and paralog-based synthetic lethality is a promising strategy for treating CDK12 mutant mCRPC.
2024-04-17 | GSE254387 | GEO