scholarly journals A histone methyltransferase inhibitor can reverse epigenetically acquired drug resistance in the malaria parasite Plasmodium falciparum

2019 ◽  
Author(s):  
Amanda Chan ◽  
Alexis Dziedziech ◽  
Laura A Kirkman ◽  
Kirk W Deitsch ◽  
Johan Ankarklev
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acquired Resistance ◽  
Anion Channel ◽  
Histone Methyltransferase ◽  
Drug Uptake ◽  
Natural Setting ◽  
Membrane Expression ◽  
Acquired Drug Resistance ◽  
Histone Modifiers

AbstractMalaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, reversing acquired resistance to the antimalarial compound blasticidin S that is transported through PSAC. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.ImportanceDrug resistance is a major concern for the treatment of infectious diseases throughout the world. For malaria, a novel mechanism of resistance was recently described in which epigenetic modifications led to a resistance phenotype that is rapidly reversible, thus reducing the fitness cost that is often associated with genetic mutations that lead to resistance. The possibility of this type of resistance arising in a natural setting is particularly troubling since parasites could rapidly switch to and from a resistant phenotype, thus making it especially difficult to combat. Here we show that application of a histone methyltransferase inhibitor can rapidly reverse the epigenetic changes that lead to drug resistance, thereby causing parasites to revert to a drug sensitive phenotype. This is a novel application of drugs that target epigenetic modifiers and lends additional support for ongoing efforts to develop drugs against malaria that target the histone modifiers of the parasite.

scholarly journals A Histone Methyltransferase Inhibitor Can Reverse Epigenetically Acquired Drug Resistance in the Malaria Parasite Plasmodium falciparum

2020 ◽  
Vol 64 (6) ◽  
Author(s):  
Amanda Chan ◽  
Alexis Dziedziech ◽  
Laura A. Kirkman ◽  
Kirk W. Deitsch ◽  
Johan Ankarklev
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acquired Resistance ◽  
Anion Channel ◽  
Histone Methyltransferase ◽  
Drug Uptake ◽  
Membrane Expression ◽  
Content Type ◽  
Acquired Drug Resistance ◽  
Parasite Plasmodium Falciparum

ABSTRACT Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 (clag3) family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds, and parasites can acquire resistance by silencing clag3 gene expression, thereby reducing drug uptake. We found that exposure to sub-IC50 concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both clag3 gene expression and RBC permeability, and reversed acquired resistance to the antimalarial compound blasticidin S that is transported through PSACs. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in P. falciparum.

scholarly journals Acquired Resistance to Clinical Cancer Therapy: A Twist in Physiological Signaling

2016 ◽  
Vol 96 (3) ◽  
pp. 805-829 ◽  
Author(s):  
Andreas Wicki ◽  
Mario Mandalà ◽  
Daniela Massi ◽  
Daniela Taverna ◽  
Huifang Tang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Immune System ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Therapeutic Strategies ◽  
Host Immune System ◽  
Cancer Therapies ◽  
Acquired Drug Resistance ◽  
Physiological Signal

Although modern therapeutic strategies have brought significant progress to cancer care in the last 30 years, drug resistance to targeted monotherapies has emerged as a major challenge. Aberrant regulation of multiple physiological signaling pathways indispensable for developmental and metabolic homeostasis, such as hyperactivation of pro-survival signaling axes, loss of suppressive regulations, and impaired functionalities of the immune system, have been extensively investigated aiming to understand the diversity of molecular mechanisms that underlie cancer development and progression. In this review, we intend to discuss the molecular mechanisms of how conventional physiological signal transduction confers to acquired drug resistance in cancer patients. We will particularly focus on protooncogenic receptor kinase inhibition-elicited tumor cell adaptation through two major core downstream signaling cascades, the PI3K/Akt and MAPK pathways. These pathways are crucial for cell growth and differentiation and are frequently hyperactivated during tumorigenesis. In addition, we also emphasize the emerging roles of the deregulated host immune system that may actively promote cancer progression and attenuate immunosurveillance in cancer therapies. Understanding these mechanisms may help to develop more effective therapeutic strategies that are able to keep the tumor in check and even possibly turn cancer into a chronic disease.

High spatiotemporal heterogeneity, clonal selection and neoantigen evolution in acquired sorafenib-resistant patient-derived xenograft models of hepatocellular carcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15641-e15641
Author(s):  
Xin-Rong Yang ◽  
Bo Hu ◽  
Jian Zhou ◽  
Jia Fan
Keyword(s):  
Drug Resistance ◽  
Clonal Selection ◽  
Acquired Resistance ◽  
Tumor Mutation Burden ◽  
Acquired Drug Resistance ◽  
Patient Derived Xenograft ◽  
Mutation Burden ◽  
Spatiotemporal Heterogeneity ◽  
Pdx Models ◽  
Syngeneic Tumors

e15641 Background: Patient-derived xenograft (PDX) models have been regarded as valuable preclinical models for oncology drug development and exploring underlying mechanism of drug resistance. As the standard treatment option for advanced hepatocellular carcinoma (HCC), the survival benefit of sorafenib is modest. Even among those who initially responded well to sorafenib treatment, most patients ultimately develop progressive disease owing to acquired drug resistance. Understanding how selective pressure from sorafenib directs the evolution of HCC and shapes its clonal architecture is a central biological question with important clinical implications to combat acquired drug resistance. Methods: Three sorafenib-resistant PDX models were generated by continuous sorafenib treament for more than six months. Whole exome sequencing (WES) and RNA sequencing were performed. The subclone of mutation, fusion genes, and the evolving landscape of tumor neoantigens were further explored. Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was evaluated in sorafenib resistance syngeneic tumors model by immune-competent C57BL/6J mice with Hepa 1-6. Results: High spatiotemporal heterogeneity was observed in engraftment among pre- and post- sorafenib resistance in established acquired-resistance PDX models. Clonal selection on engraftment was observed in established acquired-resistance PDX models. There are many high expressed genes, which showed subclone expansion with the emergence of sorafenib resistance. There is vary difference of neoantigens between pre- and post-resistance engraftment as well as sampling points in same tissues. It was presented that a high burden of clonal neoantigens in sorafenib resistant tissues (P < 0.05), while there has no difference in tumor mutation burden. Moreover, the intra-tumor heterogeneity upon the neoantigen landscape was much bigger than that upon tumor mutation burden. We found that fusion subclone sizes were increased significantly after sorafenib resistance (P < 0.05). Finally, the antitumor efficacy of recombinant mouse PD-1 antibody was confirmed in sorafenib resistance syngeneic tumors mice model (P < 0.001). Conclusions: High spatiotemporal heterogeneity, clonal selection and neoantigen evolution was observed in acquired sorafenib-resistant PDX model of HCC. Immunotherapy such as immune checkpoint inhibitors might be a promising strategy for HCC patients with acquired sorafenib resistance. .

scholarly journals APOBEC3A drives acquired resistance to targeted therapies in non-small cell lung cancer

2021 ◽  
Author(s):  
Hideko Isozaki ◽  
Ammal Abbasi ◽  
Naveed Nikpour ◽  
Adam Langenbucher ◽  
Wenjia Su ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Small Cell Lung Cancer ◽  
Targeted Therapies ◽  
Acquired Resistance ◽  
Small Cell ◽  
Tumor Evolution ◽  
Small Cell Lung ◽  
Acquired Drug Resistance

AbstractAcquired drug resistance to even the most effective anti-cancer targeted therapies remains an unsolved clinical problem. Although many drivers of acquired drug resistance have been identified1‒6, the underlying molecular mechanisms shaping tumor evolution during treatment are incompletely understood. The extent to which therapy actively drives tumor evolution by promoting mutagenic processes7 or simply provides the selective pressure necessary for the outgrowth of drug-resistant clones8 remains an open question. Here, we report that lung cancer targeted therapies commonly used in the clinic induce the expression of cytidine deaminase APOBEC3A (A3A), leading to sustained mutagenesis in drug-tolerant cancer cells persisting during therapy. Induction of A3A facilitated the formation of double-strand DNA breaks (DSBs) in cycling drug-treated cells, and fully resistant clones that evolved from drug-tolerant intermediates exhibited an elevated burden of chromosomal aberrations such as copy number alterations and structural variations. Preventing therapy-induced A3A mutagenesis either by gene deletion or RNAi-mediated suppression delayed the emergence of drug resistance. Finally, we observed accumulation of A3A mutations in lung cancer patients who developed drug resistance after treatment with sequential targeted therapies. These data suggest that induction of A3A mutagenesis in response to targeted therapy treatment may facilitate the development of acquired resistance in non-small-cell lung cancer. Thus, suppressing expression or enzymatic activity of A3A may represent a potential therapeutic strategy to prevent or delay acquired resistance to lung cancer targeted therapy.

Identification of Genomic Classifiers That Distinguish Induction Failure in T-Lineage Acute Lymphoblastic Leukemia in COG Study 9404.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1826-1826
Author(s):  
Stuart S. Winter ◽  
Hadya Khawaja ◽  
Zeyu Jiang ◽  
Timothy Griffin ◽  
Barbara Asselin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drug Resistance ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Lines ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Profiles ◽  
Resistant Cell ◽  
Acquired Drug Resistance ◽  
Induction Failure

Abstract The clinical features of age, white count, and presence of extramedullary disease cannot predict risk for induction failure (IF) in patients who present with T-cell acute lymphoblastic leukemia (T-ALL). On the basis of recent observations that gene expression profiles can distinguish clinicopathologic cohorts of patients with acute leukemia, we hypothesized that microarray analyses performed on diagnostic T-ALL bone marrow samples might identify a genomic classifier for IF patients. Using a case-control study design for children and young adults treated for T-ALL on Children’s Oncology Group Study 9404, we analyzed 50 cryopreserved T-ALL samples using Affymetrix U133A Plus 2 genechips, which have 54,000 genes, ESTs and genomic classifiers. Following RMA normalization, we used Prognostic Multi-array Analysis (PAM) to identify a 116-member genomic classifier that could accurately identify all 6 IF cases from the 44 patients who achieved remission. Within the IF cohort, 37 genes were up-regulated and 79 were down-regulated in comparison to other outcome groups. To further investigate the genetic mechanisms governing IF, we developed four cell lines with acquired drug resistance: Jurkat and Sup T1; each having resistance to daunorubicin (DNR) and asparaginase (ASP). Using a comparative analysis for fold-change in gene expression among 6 IF patients and the T-ALL DNR and ASP-resistant cell lines, we identified seven genes that were up-regulated, and another set of seven genes that were commonly down-regulated. To validate the potential use of our 116-member gene set in predicting IF in T-ALL, we tested our genomic classifier in 42 cases which were treated on COG study 8704 and hybridized to the Affymetrix U133Av.2 chip. Because only 85 probes were shared between U133A Plus 2 and U133Av. 2 chips, we employed shrunken class centroids to constrain our classifier to 25 rank-ordered probes. This smaller classifier correctly identified the single IF case in 8704, as well as another patient who was an early treatment failure, indicating that similar genomic classifiers may identify IF patients in different clinical trials. These results indicate that genetic profiling may be useful in prospectively identifying IF patients in T-ALL. In addition, we identified genes that were commonly upregulated in IF patients and T-ALL cell lines with intrinsic drug resistance.

NF-kB as a Regulator of FA/BRCA Gene Expression in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3508-3508
Author(s):  
Vasco A. Oliveira ◽  
Linda Mathews ◽  
Danielle Yarde ◽  
Xingyu Wang ◽  
David Boulware ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Dna Binding ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Binding Activity ◽  
Acquired Drug Resistance ◽  
Brca Gene ◽  
Dna Binding Activity

Abstract Results to date argue compellingly that disruption of FA/BRCA gene expression plays a pivotal role in human somatic carcinogenesis. Melphalan, a DNA cross-linker, is one of the most widely used and effective drugs in the treatment of multiple myeloma (MM). Although most patients respond to standard and high dose melphalan, eventually patients acquire resistance and develop progressive disease. In 1991, our laboratory reported that acquired resistance in a human myeloma cell line was associated with reduced DNA crosslinks, elevated glutathione levels, and increased radiation survival (Cancer Res. 5:993; 1991). Most recently, we reported that the melphalan-resistant myeloma cell lines, 8226/LR5 and U266/LR6, showed a significant increase in several FA/BRCA genes compared to drug-sensitive cells, and that enhanced interstrand crosslink (ICL) repair via this signaling pathway contributes to acquired drug resistance in melphalan resistant cell lines (Blood 10:698; 2005). Here, we report that IKKa is constitutively phosphorylated in unstimulated 8226/LR5 cells, but not in melphalan-sensitive control cells. The specific phosphorylation of IKKa leads to an increase in basal NF-kB DNA binding activity, and 8226/LR5 cells are found to be markedly sensitive to BMS-345541 (a highly selective inhibitor of IkB) relative to control cells. Importantly, a cytotoxic dose of BMS-345541 induces a dramatic decrease in FA/BRCA gene expression, and a concomitant inhibition of NF-kB DNA binding activity in both 8226/S and 8226/LR5 cells. Furthermore, we show that 8226/LR5 cells experience the highest degree of direct binding between FANCD2 promoter and NF-kB/Rel family members, which, in turn, leads to an increase in basal FANCD2-specific NF-kB activity. Small-interfering RNA (siRNA)-mediated depletion of RelB and p50, but not other NF-kB subunits, in 8226 cells results in impaired NF-kB binding activity, and visible decrease in FANCD2 protein expression. Studies designed to dissect the role of NF-kB in acquired melphalan resistance are in progress, and the results will be presented. Our findings suggest that NF-kB functions as a regulator of FA/BRCA expression, and that this pathway represents a new target for preventing acquired drug resistance in myeloma patients.

Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein

Blood ◽  
2008 ◽  
Vol 112 (6) ◽  
pp. 2489-2499 ◽  
Author(s):  
Ruud Oerlemans ◽  
Niels E. Franke ◽  
Yehuda G. Assaraf ◽  
Jacqueline Cloos ◽  
Ina van Zantwijk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Drug Resistance ◽  
Molecular Basis ◽  
Proteasome Inhibitor ◽  
Acquired Resistance ◽  
Binding Pocket ◽  
Cross Resistance ◽  
Chemotherapeutic Drugs ◽  
Proteasome Subunits

AbstractThe proteasome inhibitor bortezomib is a novel anticancer drug that has shown promise in the treatment of refractory multiple myeloma. However, its clinical efficacy has been hampered by the emergence of drug-resistance phenomena, the molecular basis of which remains elusive. Toward this end, we here developed high levels (45- to 129-fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib. Study of the molecular mechanism of bortezomib resistance in these cells revealed (1) an Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome β5-subunit (PSMB5) protein, (2) a dramatic overexpression (up to 60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7, (3) high levels of cross-resistance to β5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugs, (4) no marked changes in chymotrypsin-like proteasome activity, and (5) restoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing of PSMB5 gene expression. Collectively, these findings establish a novel mechanism of bortezomib resistance associated with the selective overexpression of a mutant PSMB5 protein.

scholarly journals DIA-based Proteomics Identifies IDH2 as a Targetable Regulator of Acquired Drug Resistance in Chronic Myeloid Leukemia

2021 ◽  
Author(s):  
wei liu ◽  
Yaoting Sun ◽  
weigang ge ◽  
fangfei zhang ◽  
lin gan ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Drug Target ◽  
Acquired Resistance ◽  
Resistance Index ◽  
K562 Cells ◽  
Resistance Mechanisms ◽  
Acquired Drug Resistance ◽  
Proteome Changes

Drug resistance is a critical obstacle to effective treatment in patients with chronic myeloid leukemia (CML). To understand the underlying resistance mechanisms in response to imatinib (IMA) and adriamycin (ADR), the parental K562 cells were treated with low doses of IMA or ADR for two months to generate derivative cells with mild, intermediate and severe resistance to the drugs as defined by their increasing resistance index (RI). PulseDIA-based quantitative proteomics was then employed to reveal the proteome changes in these resistant cells. In total, 7,082 proteotypic proteins from 98,232 peptides were identified and quantified from the dataset using four DIA software tools including OpenSWATH, Spectronaut, DIA-NN, and EncyclopeDIA. Sirtuin Signaling Pathway was found to be significantly enriched in both ADR- and IMA-resistant K562 cells. In particular, IDH2 was identified as a potential drug target correlated with the drug resistance phenotype, and its inhibition by the antagonist AGI-6780 reversed the acquired resistance in K562 cells to either ADR or IMA. Together, our study has implicated IDH2 as a potential target that can be therapeutically leveraged to alleviate the drug resistance in K562 cells when treated with IMA and ADR.

scholarly journals DIFFERENT MORPHOLOGICAL STRUCTURES OF BREAST TUMORS DEMONSTRATE INDIVIDUAL DRUG RESISTANCE GENE EXPRESSION PROFILES

2018 ◽  
Vol 40 (3) ◽  
pp. 228-234 ◽  
Author(s):  
T S Gerashchenko ◽  
E V Denisov ◽  
N M Novikov ◽  
L A Tashireva ◽  
E V Kaigorodova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Drug Resistance ◽  
Anticancer Drugs ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Drug Uptake ◽  
Functional Enrichment ◽  
Differentially Expressed ◽  
Luminal Breast Cancer

Aim: To identify gene expression profiles involved in drug resistance of different morphological structures (tubular, alveolar, solid, trabecular, and discrete) presented in breast cancer. Material and Methods: Ten patients with luminal breast cancer have been included. A laser microdissection-assisted microarrays and qRT-PCR were used to perform whole-transcriptome profiling of different morphological structures, to select differentially expressed drug response genes, and to validate their expression. Results: We found 27 differentially expressed genes (p < 0.05) encoding drug uptake (SLC1A3, SLC23A2, etc.) and efflux (ABCC1, ABCG1, etc.) transporters, drug targets (TOP2A, TYMS, and Tubb3), and proteins that are involved in drug detoxification (NAT1 and ALDH1B1), cell cycle progression (CCND1, AKT1, etc.), apoptosis (CASP3, TXN2, etc.), and DNA repair (BRCA1 and USP11). Each type of structures showed an individual gene expression profile related to resistance and sensitivity to anticancer drugs. However, most of the genes (19/27; p < 0.05) were expressed in alveolar structures. Functional enrichment analysis showed that drug resistance is significantly associated with alveolar structures. Other structures demonstrated the similar number (10–13 out of 27) of expressed genes; however, the spectrum of resistance and sensitivity to different anticancer drugs varied. Conclusion: Different morphological structures of breast cancer show individual expression of drug resistance genes.

scholarly journals Acquired Drug Resistance During the Turnaround Time for Drug Susceptibility Testing Impacts Outcome of Tuberculosis

2021 ◽  
Author(s):  
Jiahui Zhu ◽  
Lina Davies Forsman ◽  
Ziwei Bao ◽  
Yan Xie ◽  
Zhu Ning ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Treatment Outcome ◽  
Acquired Resistance ◽  
Drug Susceptibility ◽  
Turnaround Time ◽  
Drug Susceptibility Testing ◽  
Sputum Culture ◽  
Acquired Drug Resistance ◽  
Culture Conversion

Abstract BackgroundThe impacts of acquired resistance to first-line drugs (FLDs) during turnaround time (TAT) for drug susceptibility testing (DST) are still unclear. Thus, we aimed to investigate the impacts of acquired resistance to FLDs during TAT for DST on tuberculosis (TB) standard treatment.MethodWe performed a prospective cohort study between 2013 and 2018 in China, including sputum culture-positive TB patients with a baseline DST result for a Mycobacterium tuberculosis (Mtb) isolate collected at TB diagnosis and a follow-up DST result for a Mtb isolate collected when baseline DST result became available. Mtb isolates with acquired drug resistance were identified by the comparison between baseline and follow-up DST. Treatment outcome were evaluated by sputum culture conversion and World Health Organization (WHO) treatment outcome definitions. ResultsIn total, 65 patients with Mtb isolates with acquired resistance to any FLDs and 130 patients with consistent drug susceptibility profile were included in the analysis. In a Cox proportional hazard regression analysis, acquired pyrazinamide-resistance (aHR 0.54, 95%CI: 0.36-0.81) and acquired isoniazid-resistance (aHR 0.50, 95%CI: 0.29-0.85) were associated with prolonged time to sputum culture conversion. Furthermore, independent risk factors of treatment failure included acquired INH-resistance (aOR 7.64, 95%CI: 2.39-16.08) and acquired PZA-resistance (aOR 5.71, 95%CI: 2.31-14.12).ConclusionThe association between acquisition of drug resistance and treatment outcome highlights the importance of shortening the turnaround time of DST.

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