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Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [bulk]

ABSTRACT: Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Aberrant CDK12 expression, homozygous loss, and mutations have been documented in various malignancies. Previous studies have demonstrated CDK12 and 13 are promising therapeutic targets in cancer. In this study, we developed a selective CDK12/13 PROTAC degrader YJ9069, which in a panel of cancer cell lines, affirm its effectiveness in inhibiting cell proliferation in subsets of cancer. CDK12/13 degradation rapidly triggers gene-length dependent transcriptional elongation defects, leading to DNA damage and cell cycle arrest. In vivo, YJ9069 significantly suppresses tumor growth in prostate cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Modifications of YJ9069 yielded a first-in-class orally bioavailable CDK12/13 degrader, YJ1206, which exhibits a comparable efficacy with significantly less toxicity. To identify pathways that may be synthetically lethal upon CDK12/13 degradation, we screened phosphorylation pathway arrays employing cell lines treated with YJ1206. Interestingly, degradation or genetic knock-down of CDK12/13, led to activation of the Akt pathway. Degradation of CDK12/13 with YJ1206, combined with AKT pathway inhibition with uprosertib, led to a striking synthetic lethal effect in pre-clinical models of prostate cancer. Taken together, these studies demonstrate that combination CDK12/13 and AKT pathway antagonism induces drug-drug synthetic lethality.

ORGANISM(S): Homo sapiens

PROVIDER: GSE262119 | GEO | 2024/08/14

REPOSITORIES: GEO

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Development of an orally bioavailable CDK12/13 degrader and induction of synthetic lethality with AKT pathway inhibition [nascent]

Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play pivotal roles in orchestrating transcription elongation, DNA damage response, and maintenance of genomic stability. Aberrant CDK12 expression, homozygous loss, and mutations have been documented in various malignancies. Previous studies have demonstrated CDK12 and 13 are promising therapeutic targets in cancer. In this study, we developed a selective CDK12/13 PROTAC degrader YJ9069, which in a panel of cancer cell lines, affirm its effectiveness in inhibiting cell proliferation in subsets of cancer. CDK12/13 degradation rapidly triggers gene-length dependent transcriptional elongation defects, leading to DNA damage and cell cycle arrest. In vivo, YJ9069 significantly suppresses tumor growth in prostate cancer cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models. Modifications of YJ9069 yielded a first-in-class orally bioavailable CDK12/13 degrader, YJ1206, which exhibits a comparable efficacy with significantly less toxicity. To identify pathways that may be synthetically lethal upon CDK12/13 degradation, we screened phosphorylation pathway arrays employing cell lines treated with YJ1206. Interestingly, degradation or genetic knock-down of CDK12/13, led to activation of the Akt pathway. Degradation of CDK12/13 with YJ1206, combined with AKT pathway inhibition with uprosertib, led to a striking synthetic lethal effect in pre-clinical models of prostate cancer. Taken together, these studies demonstrate that combination CDK12/13 and AKT pathway antagonism induces drug-drug synthetic lethality.

2024-08-14 | GSE262120 | GEO

EWS/FLI confers tumor cell synthetic lethality to CDK12 inhibition in Ewing sarcoma

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Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ChIP-Seq]

Project description:Lung cancer is the top cause of cancer mortality. Despite recent advances, the majority of patients with lung cancer still lack effective therapeutic options, underscoring the dire need for additional treatment approaches. Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer with a frequency of up to 33% in advanced stage disease, making it the most frequently mutated complex in lung cancer. Recent reports have identified the paralogue SMARCA2 to be synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. To overcome this hurdle, we have utilized iterative structure-activity relationship (SAR) studies to develop novel, potent and selective SMARCA2 degrading small molecules based on proteolysis targeting chimera (PROTAC) technology. We demonstrated that YD23, our lead SMARCA2 PROTAC, potently and selectively induces degradation of SMARCA2. Mechanistically, we show that SMARCA2 degradation in SMARCA4-mutant cells induces a profound reprograming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified nuclear effectors of the Hippo pathway, YAP/TEAD, as key co-conspirators of SMARCA2 in driving the growth of SMARCA4-mutant cancer cells that can be disrupted by our degrader. Finally, we show that YD23 has a potent tumor growth inhibitory activity in SMARCA4-mutant xenograft tumors. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4 mutant tumors.

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Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [RNA-Seq]

2024-09-27 | GSE236587 | GEO

Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer [ATAC-Seq]

2024-09-27 | GSE236588 | GEO

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality [scRNA-Seq]

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

CDK12 Loss Promotes Prostate Cancer Development While Exposing Vulnerabilities to Paralog-Based Synthetic Lethality [RNA-Seq]

2024-04-17 | GSE254388 | GEO

Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells [PRO-seq]

Project description:We report the development of a second-generation AKT degrader INY-05-040, which outperformed catalytic AKT inhibition both with respect to biochemical and cellular suppression of AKT/mTORC1-driven phenotypes in diverse breast cancer cell lines. Using multi-omic profiling and causal network integration, we demonstrate that the enhanced efficacy of INY-05-040 relies in part on potent downstream activation of stress mitogen activated protein kinase (MAPK) signaling. Systematic measurements of growth inhibition across 288 cancer cell lines confirmed the substantial improvement in potency for INY-05-040 compared to the first-generation AKT degrader (INY-03-041) and catalytic AKT inhibition with GDC-0068. Subsequent integration of breast cancer cell line-specific data with publicly available transcriptomic, proteomic and reverse phase protein array (RPPA) measurements revealed that decreased sensitivity to INY-05-040 correlates with a high baseline activation of inflammatory/stress signaling pathways. Collectively, our data uncover a unique mechanism of breast cancer cell line sensitivity to AKT degradation, further suggesting that the efficacy of catalytic AKT inhibition may be enhanced by activation of stress MAPKs in breast cancer cells with low baseline activity of these components.

2022-10-15 | GSE206388 | GEO

Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells [RNA-seq]

2022-10-15 | GSE206385 | GEO

CDK12 regulates co-transcriptional splicing and RNA turnover in human cells

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

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