It is now well recognized that mutations, deregulated expression, and aberrant recruitment of epigenetic readers, writers, and erasers are fundamentally important processes in the onset and ...maintenance of many human tumors. The molecular, biological, and biochemical characteristics of a particular class of epigenetic erasers, the histone deacetylases (HDACs), have been extensively studied and small‐molecule HDAC inhibitors (HDACis) have now been clinically approved for the treatment of human hemopoietic malignancies. This review explores our current understanding of the biological and molecular effects on tumor cells following HDACi treatment. The predominant responses include induction of tumor cell death and inhibition of proliferation that in experimental models have been linked to therapeutic efficacy. However, tumor cell‐intrinsic responses to HDACi, including modulating tumor immunogenicity have also been described and may have substantial roles in mediating the antitumor effects of HDACi. We posit that the field has failed to fully reconcile the biological consequences of exposure to HDACis with the molecular events that underpin these responses, however progress is being made. Understanding the pleiotrophic activities of HDACis on tumor cells will hopefully fast track the development of more potent and selective HDACi that may be used alone or in combination to improve patient outcomes.
Histone deacetylases (HDAC) inhibitors can mediate antitumor effects by inducing a variety of different biological responses leading to suppression of cell proliferation and cell survival and/or enhanced tumor cell immunogenicity. Any one or more of these responses to HDAC inhibition may ultimately lead to positive therapeutic outcomes for patients with a range of different hematological and solid tumors.
Histone deacetylases (HDACs) are enzymes involved in the remodelling of chromatin, and have a key role in the epigenetic regulation of gene expression. In addition, the activity of non-histone ...proteins can be regulated through HDAC-mediated hypo-acetylation. In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specific anticancer activities in preclinical studies. However, such studies have also indicated that the effects of HDAC inhibitors could be considerably broader and more complicated than originally understood. Here we summarize recent advances in the understanding of the molecular events that underlie the anticancer effects of HDAC inhibitors, and discuss how such information could be used in optimizing the development and application of these agents in the clinic, either as monotherapies or in combination with other anticancer drugs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Cancer cell hallmarks are underpinned by transcriptional programmes operating in the context of a dynamic and complicit epigenomic environment. Somatic alterations of chromatin modifiers are among ...the most prevalent cancer perturbations. There is a pressing need for targeted chemical probes to dissect these complex, interconnected gene regulatory circuits. Validated chemical probes empower mechanistic research while providing the pharmacological proof of concept that is required to translate drug-like derivatives into therapy for cancer patients. In this Review, we describe chemical probe development for epigenomic effector proteins that are linked to cancer pathogenesis. By annotating these reagents, we aim to share our perspectives on an informative 'epigenomic toolbox' of broad utility to the research community.
Despite the clinical success of cancer immunotherapies, the majority of patients fail to respond or develop resistance through disruption of pathways that promote neo-antigen presentation on MHC I ...molecules. Here, we conducted a series of unbiased, genome-wide CRISPR/Cas9 screens to identify genes that limit natural killer (NK) cell anti-tumor activity. We identified that genes associated with antigen presentation and/or interferon-γ (IFN-γ) signaling protect tumor cells from NK cell killing. Indeed, Jak1-deficient melanoma cells were sensitized to NK cell killing through attenuated NK cell-derived IFN-γ-driven transcriptional events that regulate MHC I expression. Importantly, tumor cells that became resistant to T cell killing through enrichment of MHC I-deficient clones were highly sensitive to NK cell killing. Taken together, we reveal the genes targeted by tumor cells to drive checkpoint blockade resistance but simultaneously increase their vulnerability to NK cells, unveiling NK cell-based immunotherapies as a strategy to antagonize tumor immune escape.
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•CRISPR screening allows discovery of tumor genes that limit NK cell effector function•Disruption of IFN-γ signaling and/or MHC-I triggers sensitivity to NK cells•Evasion of T cell immunity promotes tumor vulnerability to NK cells•NK cell-targeted immunotherapies may antagonize tumor immune evasion from T cells
Freeman et al. use a series of genome-wide loss-of-function genetic screens to identify genes that limit tumor sensitivity to killing by natural killer cells. The findings highlight that natural killer cells can suppress tumor immune evasion from T cells, identifying a potential strategy to overcome resistance to checkpoint blockade therapy.
Abstract Histone deacetylase inhibitors (HDACi) are anti-cancer drugs that have moved rapidly through clinical development and in 2006 vorinostat (SAHA, Zolinza) was given FDA approval for the ...treatment of cutaneous T cell lymphoma. Class I, II and IV HDACs that are targets for these compounds deacetylate histone proteins, resulting in chromatin remodelling and altered gene transcription. In addition, numerous non-histone proteins are modified by acetylation and the inhibition of HDAC activity can therefore affect various molecular processes. This broad effect on protein function may account for the pleiotropic anti-tumor responses elicited by HDACi that include induction of tumor cell apoptosis, cell cycle arrest, differentiation and senescence, modulation of immune responses and altered angiogenesis. The ability of HDACi to selectively induce tumor cells to undergo apoptosis is important for the therapeutic efficacy observed in pre-clinical models. Moreover, HDACi can augment the apoptotic effects of other anti-cancer agents that have diverse molecular targets. While HDACi are promising anti-cancer drugs, particularly given the scope to combine HDACi with other agents, identifying the key molecular events that determine the biological response of cells to HDACi treatment remains a challenge. Herein we focus on HDACi-induced apoptosis and discuss the various proteins and pathways that are affected by HDACi to mediate this programmed cell death response. In addition, we highlight the ability of HDACi to synergise with other anti-cancer agents to potently kill tumor cells and discuss the possible molecular processes that underpin the combination effect.
BET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma ...model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.
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•BETi require an intact host immune system to promote robust anti-tumor responses•BRD4 inhibition inhibits PD-L1 transcription independently from MYC expression•BRD4 and IRF1 co-regulate interferon-induced PD-L1 transcription•Combinations of BET inhibitor and immune modulating therapy are efficacious in vivo
Hogg et al. find that BET bromodomain inhibitors promote anti-tumor immune responses through transcriptional repression of immune checkpoint ligand PD-L1 in genetically diverse tumor models and in response to inflammatory stimuli. Moreover, BET inhibitors enhance the efficacy of immune modulating therapies, such as checkpoint blockade.
It is becoming increasingly evident that radiotherapy may benefit from coincident or subsequent immunotherapy. In this study, we examined whether the antitumor effects of radiotherapy, in established ...triple-negative breast tumors could be enhanced with combinations of clinically relevant monoclonal antibodies (mAb), designed to stimulate immunity anti-(α)-CD137, α-CD40 or relieve immunosuppression α-programmed death (PD)-1. While the concomitant targeting of the costimulatory molecules CD137 and CD40 enhanced the antitumor effects of radiotherapy and promoted the rejection of subcutaneous BALB/c-derived 4T1.2 tumors, this novel combination was noncurative in mice bearing established C57BL/6-derived AT-3 tumors. We identified PD-1 signaling within the AT-3 tumors as a critical limiting factor to the therapeutic efficacy of α-CD137 therapy, alone and in combination with radiotherapy. Strikingly, all mice bearing established orthotopic AT-3 mammary tumors were cured when α-CD137 and α-PD-1 mAbs were combined with single- or low-dose fractionated radiotherapy. CD8+ T cells were essential for curative responses to this combinatorial regime. Interestingly, CD137 expression on tumor-associated CD8+ T cells was largely restricted to a subset that highly expressed PD-1. These CD137+PD-1High CD8+ T cells, persisted in irradiated AT-3 tumors, expressed Tim-3, granzyme B and Ki67 and produced IFN-γ ex vivo in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin stimulation. Notably, radiotherapy did not deplete, but enriched tumors of functionally active, tumor-specific effector cells. Collectively, these data show that concomitant targeting of immunostimulatory and inhibitory checkpoints with immunomodulatory mAbs can enhance the curative capacity of radiotherapy in established breast malignancy.
Human immunodeficiency virus (HIV) persistence in latently infected resting memory CD4+ T-cells is the major barrier to HIV cure. Cellular histone deacetylases (HDACs) are important in maintaining ...HIV latency and histone deacetylase inhibitors (HDACi) may reverse latency by activating HIV transcription from latently infected CD4+ T-cells. We performed a single arm, open label, proof-of-concept study in which vorinostat, a pan-HDACi, was administered 400 mg orally once daily for 14 days to 20 HIV-infected individuals on suppressive antiretroviral therapy (ART). The primary endpoint was change in cell associated unspliced (CA-US) HIV RNA in total CD4+ T-cells from blood at day 14. The study is registered at ClinicalTrials.gov (NCT01365065). Vorinostat was safe and well tolerated and there were no dose modifications or study drug discontinuations. CA-US HIV RNA in blood increased significantly in 18/20 patients (90%) with a median fold change from baseline to peak value of 7.4 (IQR 3.4, 9.1). CA-US RNA was significantly elevated 8 hours post drug and remained elevated 70 days after last dose. Significant early changes in expression of genes associated with chromatin remodeling and activation of HIV transcription correlated with the magnitude of increased CA-US HIV RNA. There were no statistically significant changes in plasma HIV RNA, concentration of HIV DNA, integrated DNA, inducible virus in CD4+ T-cells or markers of T-cell activation. Vorinostat induced a significant and sustained increase in HIV transcription from latency in the majority of HIV-infected patients. However, additional interventions will be needed to efficiently induce virus production and ultimately eliminate latently infected cells.
ClinicalTrials.gov NCT01365065.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Targeting transcription cycles in cancer Vervoort, Stephin J; Devlin, Jennifer R; Kwiatkowski, Nicholas ...
Nature reviews. Cancer,
01/2022, Letnik:
22, Številka:
1
Journal Article
Recenzirano
Accurate control of gene expression is essential for normal development and dysregulation of transcription underpins cancer onset and progression. Similar to cell cycle regulation, RNA polymerase ...II-driven transcription can be considered as a unidirectional multistep cycle, with thousands of unique transcription cycles occurring in concert within each cell. Each transcription cycle comprises recruitment, initiation, pausing, elongation, termination and recycling stages that are tightly controlled by the coordinated action of transcriptional cyclin-dependent kinases and their cognate cyclins as well as the opposing activity of transcriptional phosphatases. Oncogenic dysregulation of transcription can entail defective control of gene expression, either at select loci or more globally, impacting a large proportion of the genome. The resultant dependency on the core-transcriptional machinery is believed to render 'transcriptionally addicted' cancers sensitive to perturbation of transcription. Based on these findings, small molecules targeting transcriptional cyclin-dependent kinases and associated proteins hold promise for the treatment of cancer. Here, we utilize the transcription cycles concept to explain how dysregulation of these finely tuned gene expression processes may drive tumorigenesis and how therapeutically beneficial responses may arise from global or selective transcriptional perturbation. This conceptual framework helps to explain tumour-selective transcriptional dependencies and facilitates the rational design of combination therapies.
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