CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma

Thieme, Elana; Bruss, Nur; Sun, Duanchen; Dominguez, Edward C.; Coleman, Daniel J.; Liu, Tingting; Roleder, Carly; Martinez, Mélissa; Garcia-Mansfield, Krystine; Ball, Brian; Pirrotte, Patrick; Wang, Lili; Xia, Zheng; Danilov, Alexey V.

doi:10.1186/s12943-023-01762-6

Cited by 13 publications

(7 citation statements)

References 52 publications

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“…We also provide the first RNAPII ChIP-seq data in a breast cancer context that demonstrates genome-wide promoter pausing following inhibition of CDK9. This genomic data accords with recent studies that demonstrate widespread RNAPII promoter pausing induced in cell line models of blood cancer upon treatment with different CDK9 inhibitors [ 45 , 46 ]. Importantly, daily oral administration of CDDD11-8 was not associated with overt toxicity in mice at the doses tested.…”

Section: Discussionsupporting

confidence: 90%

“…A multiplicity of tumour-intrinsic factors may influence relative response to CDK9 inhibition in TNBC [ 23 ]. For example, studies suggest that activity of a bromodomain protein (BRD4) or mediator complex protein (MED12) may dampen response to CDK9 inhibition [ 45 , 50 ] and conversely that Protein Phosphatase 2 A (PP2A) activity [ 46 ] or the presence of wild-type P53 [ 51 ] may enhance response to this therapeutic strategy. Inhibition of the PIM3 kinase pathway has been shown to inhibit TNBC by indirectly targeting MYC [ 21 ] and to enhance response to a CDK9 inhibitor in models of lymphoma [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

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Selective inhibition of CDK9 in triple negative breast cancer

Mustafa,

Laven-Law,

Kikhtyak

et al. 2023

Oncogene

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Targeted therapy for triple-negative breast cancers (TNBC) remains a clinical challenge due to tumour heterogeneity. Since TNBC have key features of transcriptionally addicted cancers, targeting transcription via regulators such as cyclin-dependent kinase 9 (CDK9) has potential as a therapeutic strategy. Herein, we preclinically tested a new selective CDK9 inhibitor (CDDD11-8) in TNBC using cell line, patient-derived organoid, and patient-derived explant models. In vitro, CDDD11-8 dose-dependently inhibited proliferation (IC50 range: 281–734 nM), induced cell cycle arrest, and increased apoptosis of cell lines, which encompassed the three major molecular subtypes of TNBC. On target inhibition of CDK9 activity was demonstrated by reduced RNAPII phosphorylation at a CDK9 target peptide and down-regulation of the MYC and MCL1 oncogenes at the mRNA and protein levels in all cell line models. Drug induced RNAPII pausing was evident at gene promoters, with strongest pausing at MYC target genes. Growth of five distinct patient-derived organoid models was dose-dependently inhibited by CDDD11-8 (IC50 range: 272–771 nM), including three derived from MYC amplified, chemo-resistant TNBC metastatic lesions. Orally administered CDDD11-8 also inhibited growth of mammary intraductal TNBC xenograft tumours with no overt toxicity in vivo (mice) or ex vivo (human breast tissues). In conclusion, our studies indicate that CDK9 is a viable therapeutic target in TNBC and that CDDD11-8, a novel selective CDK9 inhibitor, has efficacy in TNBC without apparent toxicity to normal tissues.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Selective inhibition of CDK9 in triple negative breast cancer

Mustafa,

Laven-Law,

Kikhtyak

et al. 2023

Oncogene

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“…79 Additionally, our results mirror recent work where inhibition of the human CDK9 ortholog produces transcriptional reprogramming, supporting a model where the inhibition or transient repression of essential genes encourages epigenetic adaptations. 80 How other transiently-silenced essential genes, including the previously identified cup1+ gene, modulates the formation of epigenetic adaptations requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Mapping the dynamics of epigenetic adaptation during heterochromatin misregulation

Larkin

Kunze

Seman

et al. 2023

Preprint

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A classical and well-established mechanism that enables cells to adapt to new and adverse conditions is the acquisition of beneficial genetic mutations. Much less is known about epigenetic mechanisms that allow cells to develop novel and adaptive phenotypes without altering their genetic blueprint. It has been recently proposed that histone modifications, such as heterochromatin-defining H3K9 methylation (H3K9me), normally reserved to maintain genome integrity, can be redistributed across the genome to establish new and potentially adaptive phenotypes. To uncover the dynamics of this process, we developed a precision engineered genetic approach to trigger H3K9me redistribution on demand in fission yeast. This enabled us to trace genome-scale RNA and chromatin changes over time prior to and during adaptation in long-term continuous cultures. Establishing adaptive H3K9me occurs over remarkably slow time-scales relative to the initiating stress. During this time, we captured dynamic H3K9me redistribution events ultimately leading to cells converging on an optimal adaptive solution. Upon removal of stress, cells relax to new transcriptional and chromatin states rather than revert to their initial (ground) state, establishing a tunable memory for a future adaptive epigenetic response. Collectively, our tools uncover the slow kinetics of epigenetic adaptation that allow cells to search for and heritably encode adaptive solutions, with implications for drug resistance and response to infection.

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“…CDK9 inhibitor also exerted antitumor activity by inhibiting RNA polymerase (Pol) II phosphorylation and suppressed SE-mediated, tumor-specific gene expression [ 103 ]. AZD4573, a highly selective and potent CDK9 inhibitor [ 104 ] which suppressed promoter activation and sustained reprograming of the SE landscape led to epigenetic remodeling.…”

Section: Introductionmentioning

confidence: 99%

“…AZD4573, a highly selective and potent CDK9 inhibitor [ 104 ] which suppressed promoter activation and sustained reprograming of the SE landscape led to epigenetic remodeling. AZD4573 could downregulate multiple oncoproteins (MYC, Mcl-1, JunB, PIM3) and deregulate PI3K pathways in diffuse large B-cell lymphoma (DLBCL) [ 103 ]. Alvocidib was another CDK9 inhibitor that exerted antitumor activity by inhibiting IRF4 expression in adult T-cell leukemia/lymphoma via SE suppression [ 105 ].…”

Section: Introductionmentioning

confidence: 99%

Super enhancer lncRNAs: a novel hallmark in cancer

Song,

Han,

Yang

2024

Cell Commun Signal

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Super enhancers (SEs) consist of clusters of enhancers, harboring an unusually high density of transcription factors, mediator coactivators and epigenetic modifications. SEs play a crucial role in the maintenance of cancer cell identity and promoting oncogenic transcription. Super enhancer lncRNAs (SE-lncRNAs) refer to either transcript from SEs locus or interact with SEs, whose transcriptional activity is highly dependent on SEs. Moreover, these SE-lncRNAs can interact with their associated enhancer regions in cis and modulate the expression of oncogenes or key signal pathways in cancers. Inhibition of SEs would be a promising therapy for cancer. In this review, we summarize the research of SE-lncRNAs in different kinds of cancers so far and decode the mechanism of SE-lncRNAs in carcinogenesis to provide novel ideas for the cancer therapy.

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CDK9 inhibition induces epigenetic reprogramming revealing strategies to circumvent resistance in lymphoma

Cited by 13 publications

References 52 publications

Selective inhibition of CDK9 in triple negative breast cancer

Selective inhibition of CDK9 in triple negative breast cancer

Mapping the dynamics of epigenetic adaptation during heterochromatin misregulation

Super enhancer lncRNAs: a novel hallmark in cancer

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