bims-drucaf 2020-07-19 papers

bims-drucaf

Biomed News

on Drugs targeting chromatin associated factor in cancer therapy

Issue of 2020‒07‒19
eight papers selected by
Tian Tian
Vall d’Hebron Institute of Oncology

PRMT5 inhibition modulates E2F1 methylation and gene regulatory networks leading to therapeutic efficacy in JAK2V617F mutant MPN.
Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer.
DNA methyltransferase mediates the hypermethylation of the microRNA 34a promoter and enhances the resistance of patient-derived pancreatic cancer cells to molecular targeting agents.
ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer.
Histone deacetylase inhibitor based prodrugs.
Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance.
AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing.
4SC-202 induces apoptosis in myelodysplastic syndromes and the underlying mechanism.

Cancer Discov. 2020 Jul 15. pii: CD-20-0026. [Epub ahead of print]

PRMT5 inhibition modulates E2F1 methylation and gene regulatory networks leading to therapeutic efficacy in JAK2V617F mutant MPN.

Friederike Pastore, Neha Bhagwat, Alessandro Pastore, Aliaksandra Radzisheuskaya, Abdul Karzai, Aishwarya Krishnan, Bing Li, Robert L Bowman, Wenbin Xiao, Aaron D Viny, Anouar Zouak, Young C Park, Keith B Cordner, Stephanie Braunstein, Jesper L V Maag, Alexander Grego, Jaanvi Mehta, Min Wang, Hong Lin, Benjamin H Durham, Richard P Koche, Raajit K Rampal, Kristian Helin, Peggy Scherle, Kris Vaddi, Ross L Levine.

We investigated the role of PRMT5 in MPN pathogenesis and aimed to elucidate key PRMT5 targets contributing to MPN maintenance. PRMT5 is overexpressed in primary MPN cells and PRMT5 inhibition potently reduced MPN cell proliferation ex vivo. PRMT5 inhibition was efficacious at reversing elevated hematocrit, leukocytosis and splenomegaly in a model of JAK2V617F+ polycythemia vera (PV) and leukocyte and platelet counts, hepatosplenomegaly and fibrosis in the MPLW515L model of myelofibrosis (MF). Dual targeting of JAK and PRMT5 was superior to JAK or PRMT5 inhibitor monotherapy, further decreasing elevated counts and extramedullary hematopoiesis in vivo. PRMT5 inhibition reduced expression of E2F targets and altered the methylation status of E2F1 leading to attenuated DNA damage repair, cell cycle arrest and increased apoptosis. Our data link PRMT5 to E2F1 regulatory function and MPN cell survival and provide a strong mechanistic rationale for clinical trials of PRMT5 inhibitors in MPN.

DOI: https://doi.org/10.1158/2159-8290.CD-20-0026
Front Oncol. 2020 ;10 992

Understanding the Mechanisms by Which Epigenetic Modifiers Avert Therapy Resistance in Cancer.

Anthony Quagliano, Anilkumar Gopalakrishnapillai, Sonali P Barwe.

  The development of resistance to anti-cancer therapeutics remains one of the core issues preventing the improvement of survival rates in cancer. Therapy resistance can arise in a multitude of ways, including the accumulation of epigenetic alterations in cancer cells. By remodeling DNA methylation patterns or modifying histone proteins during oncogenesis, cancer cells reorient their epigenomic landscapes in order to aggressively resist anti-cancer therapy. To combat these chemoresistant effects, epigenetic modifiers such as DNA hypomethylating agents, histone deacetylase inhibitors, histone demethylase inhibitors, along with others have been used. While these modifiers have achieved moderate success when used either alone or in combination with one another, the most positive outcomes were achieved when they were used in conjunction with conventional anti-cancer therapies. Epigenome modifying drugs have succeeded in sensitizing cancer cells to anti-cancer therapy via a variety of mechanisms: disrupting pro-survival/anti-apoptotic signaling, restoring cell cycle control and preventing DNA damage repair, suppressing immune system evasion, regulating altered metabolism, disengaging pro-survival microenvironmental interactions and increasing protein expression for targeted therapies. In this review, we explore different mechanisms by which epigenetic modifiers induce sensitivity to anti-cancer therapies and encourage the further identification of the specific genes involved with sensitization to facilitate development of clinical trials.

Keywords:  cancer; chemoresistance; epigenetic aberrations; epigenetic combination therapies; epigenetic drugs; mechanism

DOI:  https://doi.org/10.3389/fonc.2020.00992
Pharmacol Res. 2020 Jul 10. pii: S1043-6618(20)31379-7. [Epub ahead of print] 105071

DNA methyltransferase mediates the hypermethylation of the microRNA 34a promoter and enhances the resistance of patient-derived pancreatic cancer cells to molecular targeting agents.

Yan Ma, Ningli Chai, Qiyu Jiang, Zhengyao Chang, Yantao Chai, Xiaojuan Li, Huiwei Sun, Jun Hou, Enqiang Linghu.

  DNA methyltransferase (DNMT) participates in the transformation or progression of human cancers by mediating the hypermethylation of cancer suppressors. However, the regulatory role of DNMT in pancreatic cancer cells remains poorly understood. In the present study, we demonstrated that DNMT1 repressed the expression of microRNA 34a (miR-34a) and enhanced the activation of the Notch pathway by mediating the hypermethylation of the miR-34a promoter. In patients with pancreatic cancer, the expression levels of DNMT1 were negatively related with those of miR-34a. Mechanistically, knockdown of DNMT1 decreased the methylation of the miR-34a promoter and enhanced the expression of miR-34a to inhibit the activation of the Notch pathway. Downregulation of the Notch pathway via the DNMT1/miR-34a axis significantly enhanced the sensitivity of pancreatic cells to molecular targeting agents. Therefore, the results of our study suggest that downregulation of DNMT enhances the expression of miR-34a and may be a potential therapeutic target for pancreatic cancer.

Keywords:  DNA methyltransferase; Drug resistance; Notch pathway; Pancreatic cancer; miR-34a

DOI:  https://doi.org/10.1016/j.phrs.2020.105071
Genome Med. 2020 Jul 15. 12(1): 63

ASXL3 bridges BRD4 to BAP1 complex and governs enhancer activity in small cell lung cancer.

Aileen Patricia Szczepanski, Zibo Zhao, Tori Sosnowski, Young Ah Goo, Elizabeth Thomas Bartom, Lu Wang.

  BACKGROUND: Small cell lung cancer (SCLC) is a more aggressive subtype of lung cancer that often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. Consequently, such phenotypical characteristics of SCLC set limitations on viable procedural options, making it difficult to develop both screenings and effective treatments. In this study, we examine a novel mechanistic insight in SCLC cells that could potentially provide a more sensitive therapeutic alternative for SCLC patients.METHODS: Biochemistry studies, including size exclusion chromatography, mass spectrometry, and western blot analysis, were conducted to determine the protein-protein interaction between additional sex combs-like protein 3 (ASXL3) and bromodomain-containing protein 4 (BRD4). Genomic studies, including chromatin immunoprecipitation sequencing (ChIP-seq), RNA sequencing, and genome-wide analysis, were performed in both human and mouse SCLC cells to determine the dynamic relationship between BRD4/ASXL3/BAP1 epigenetic axis in chromatin binding and its effects on transcriptional activity.
RESULTS: We report a critical link between BAP1 complex and BRD4, which is bridged by the physical interaction between ASXL3 and BRD4 in an SCLC subtype (SCLC-A), which expresses a high level of ASCL1. We further showed that ASXL3 functions as an adaptor protein, which directly interacts with BRD4's extra-terminal (ET) domain via a novel BRD4 binding motif (BBM), and maintains chromatin occupancy of BRD4 to active enhancers. Genetic depletion of ASXL3 results in a genome-wide reduction of histone H3K27Ac levels and BRD4-dependent gene expression in SCLC. Pharmacologically induced inhibition with BET-specific chemical degrader (dBET6) selectively inhibits cell proliferation of a subtype of SCLC that is characterized with high expression of ASXL3.
CONCLUSIONS: Collectively, this study provides a mechanistic insight into the oncogenic function of BRD4/ASXL3/BAP1 epigenetic axis at active chromatin enhancers in SCLC-A subtype, as well as a potential new therapeutic option that could become more effective in treating SCLC patients with a biomarker of ASXL3-highly expressed SCLC cells.

Keywords:  ASXL3; BAP1 complex; BET inhibitors; BRD4; Enhancer activity; SCLC

DOI:  https://doi.org/10.1186/s13073-020-00760-3
Eur J Med Chem. 2020 Jul 12. pii: S0223-5234(20)30600-0. [Epub ahead of print]203 112628

Histone deacetylase inhibitor based prodrugs.

Wenli Fan, Lihui Zhang, Qixao Jiang, Weiguo Song, Fang Yan, Lei Zhang.

  Histone deacetylases (HDACs) are a family of enzymes which play important roles in the development and progression of cancers. Inhibition of HDACs has been widely studied as a therapeutic strategy in the discovery of anticancer drugs. HDAC inhibitors (HDACIs) have exhibited potency against a variety of cancer types, and four of them have been approved by the US FDA for cancer treatment. However, the clinical benefits of current HDACIs is limited by the insufficient physicochemical property, selectivity and potency. To improve the clinical potential of HDACIs, the prodrug strategy had been utilized to improve the in vivo pharmacokinetic and pharmacodynamic performances of HDACIs. Enhancements in the stability, water solubility, lipophilicity, oral bioavailability and tumor cell selectivity were reported by various studies. Herein, the development of different kinds of HDACI-based prodrug is summarized for the further structural modification of HDACIs with high potential to be drug candidates.

Keywords:  Histone deacetylase inhibitor; Physicochemical property; Prodrug; Selectivity; Structural modification

DOI:  https://doi.org/10.1016/j.ejmech.2020.112628
Genome Biol. 2020 Jul 15. 21(1): 174

Single-cell lineage analysis reveals genetic and epigenetic interplay in glioblastoma drug resistance.

Christine E Eyler, Hironori Matsunaga, Volker Hovestadt, Samantha J Vantine, Peter van Galen, Bradley E Bernstein.

  BACKGROUND: Tumors can evolve and adapt to therapeutic pressure by acquiring genetic and epigenetic alterations that may be transient or stable. A precise understanding of how such events contribute to intratumoral heterogeneity, dynamic subpopulations, and overall tumor fitness will require experimental approaches to prospectively label, track, and characterize resistant or otherwise adaptive populations at the single-cell level. In glioblastoma, poor efficacy of receptor tyrosine kinase (RTK) therapies has been alternatively ascribed to genetic heterogeneity or to epigenetic transitions that circumvent signaling blockade.RESULTS: We combine cell lineage barcoding and single-cell transcriptomics to trace the emergence of drug resistance in stem-like glioblastoma cells treated with RTK inhibitors. Whereas a broad variety of barcoded lineages adopt a Notch-dependent persister phenotype that sustains them through early drug exposure, rare subclones acquire genetic changes that enable their rapid outgrowth over time. Single-cell analyses reveal that these genetic subclones gain copy number amplifications of the insulin receptor substrate-1 and substrate-2 (IRS1 or IRS2) loci, which activate insulin and AKT signaling programs. Persister-like cells and genomic amplifications of IRS2 and other loci are evident in primary glioblastomas and may underlie the inefficacy of targeted therapies in this disease.
CONCLUSIONS: A method for combined lineage tracing and scRNA-seq reveals the interplay between complementary genetic and epigenetic mechanisms of resistance in a heterogeneous glioblastoma tumor model.

Keywords:  Epigenetic; Genetic; Glioma stem cells; Insulin receptor substrate/IRS; Lineage tracing; Single-cell RNA-seq; Therapy resistance; Tumor heterogeneity

DOI:  https://doi.org/10.1186/s13059-020-02085-1
Cell Death Discov. 2020 ;6 57

AMG-232 sensitizes high MDM2-expressing tumor cells to T-cell-mediated killing.

Ilyas Sahin, Shengliang Zhang, Arunasalam Navaraj, Lanlan Zhou, Don Dizon, Howard Safran, Wafik S El-Deiry.

  Oncogenic mouse double minute 2 homolog (MDM2) is an E3-ubiquitin ligase that facilitates proteasomal degradation of p53. MDM2 amplification occurs in cancer and has been implicated in accelerated tumor growth, known as hyper-progression, following immune-checkpoint therapy. MDM2 amplification also predicts poor response to immune-checkpoint inhibitors. We sought to evaluate the role of MDM2 in T-cell-mediated immune resistance. Ovarian clear cell carcinoma cell lines carrying wild-type p53 with low/high MDM2 expression were investigated in a T-cell co-culture system evaluating T-cell-mediated tumor killing. Targeting of MDM2 was achieved by siRNA transfection or a selective MDM2 inhibitor, AMG-232 and tumor cells were tested in the T-cell co-culture system. AMG-232 activated p53 signaling in cancer cells and relative resistance to AMG-232 was observed in high MDM2-expressing cell lines. Cell lines with high MDM2 expression were more resistant to T cell-mediated tumor killing. Targeting MDM2 by gene-silencing or pharmacological blockade with AMG-232 enhanced T-cell killing of cancer cells. AMG-232 potentiated tumor cell killing by T-cells in combination with anti-PD-1 antibody treatment, regardless of changes in PD-L1 expression. The AMG-232 was not toxic to the T-cells. MDM2 inhibition lowered expression of Interleukin-6, a pro-inflammatory pro-tumorigenic cytokine. Our data support targeting MDM2 in tumors with overexpression or amplification of MDM2 as a precision therapy approach to overcome drug resistance including hyper-progression in the context of immune checkpoint therapy.

Keywords:  Cancer immunotherapy; Drug development

DOI:  https://doi.org/10.1038/s41420-020-0292-1
Am J Transl Res. 2020 ;12(6): 2968-2983

4SC-202 induces apoptosis in myelodysplastic syndromes and the underlying mechanism.

Weili Wang, Zhaoyuan Zhang, Xingyi Kuang, Dan Ma, Jie Xiong, Tingting Lu, Yaming Zhang, Kunling Yu, Siyu Zhang, Jishi Wang, Qin Fang.

Epigenetic modifications play crucial roles in regulating the self-renewal and differentiation of hematopoiesis. 4SC-202, a novel inhibitor of histone lysine-specific demethylase 1 (LSD1) and class I histone deacetylases (HDACs), is a potential therapeutic agent to treat myelodysplastic syndrome (MDS). However, it remains unclarified of the mechanism of 4SC-202. In the study, we found that 4SC-202 treatment could inhibit cell viability, induce apoptosis and cause G2/M cell cycle arrest in MDS cell line SKM-1. Heme oxygenase-1 (HO-1) was correlated with disease progression and chemotherapy resistance. Here, we reported that 4SC-202 could down-regulate the expression of HO-1, and up-regulation of HO-1 could significantly attenuate the 4SC-202-induced apoptosis in SKM-1 cells. In addition, the activation of NF-κB pathway was suppressed by 4SC-202, while up-regulation of HO-1 significantly weakened the 4SC-202-induced suppression of the NF-κB pathway, thereby attenuating the efficacy of 4SC-202. However, down-regulation of HO-1 enhanced the sensitivity of 4SC-202 against SKM-1 cells. Moreover, SKM-1 cells were transfected with HO-1 overexpression lentivirus, subsequently injected into the tail vein of NOD/SCID mice, followed by administration of 4SC-202 in mice. As a result, up-regulation HO-1 could partially attenuate 4SC-202-suppressed MDS cells growth in NOD/SCID mice. In conclusion, 4SC-202 could induce apoptosis via the NF-κB pathway, and our present finding may provide a novel therapeutic strategy for MDS.

Keywords: 4SC-202; NF-κB pathway; apoptosis; class I HDACs; heme oxygenase-1 (HO-1); human histone lysine-specific demethylase 1 (LSD1); myelodysplastic syndrome (MDS)