Investigating the effects of ABC transporter-based acquired drug resistance mechanisms at the cellular and tissue scale

2013 ◽  
Vol 5 (3) ◽  
pp. 555 ◽  
Author(s):  
Cong Liu ◽  
J. Krishnan ◽  
Xiao Yun Xu
Keyword(s):  
Drug Resistance ◽  
Abc Transporter ◽  
Resistance Mechanisms ◽  
Acquired Drug Resistance

scholarly journals Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Zuan-Fu Lim ◽  
Patrick C. Ma
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Minimal Residual Disease ◽  
Tumor Heterogeneity ◽  
Residual Disease ◽  
Resistance Mechanisms ◽  
Intratumoral Heterogeneity ◽  
Acquired Drug Resistance ◽  
Minimal Residual

AbstractThe biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.

scholarly journals New Insights in to the Intrinsic and Acquired Drug Resistance Mechanisms in Mycobacteria

2017 ◽  
Vol 8 ◽  
Author(s):  
Mohammad J. Nasiri ◽  
Mehri Haeili ◽  
Mona Ghazi ◽  
Hossein Goudarzi ◽  
Ali Pormohammad ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mechanisms ◽  
Acquired Drug Resistance

scholarly journals Genomic Insights into Intrinsic and Acquired Drug Resistance Mechanisms in Achromobacter xylosoxidans

2014 ◽  
Vol 59 (2) ◽  
pp. 1152-1161 ◽  
Author(s):  
Yongfei Hu ◽  
Yuying Zhu ◽  
Yanan Ma ◽  
Fei Liu ◽  
Na Lu ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Clinical Isolate ◽  
Resistance Genes ◽  
Type Strain ◽  
High Throughput Sequencing ◽  
Resistance Mechanisms ◽  
Achromobacter Xylosoxidans ◽  
Content Type ◽  
Acquired Drug Resistance ◽  
Wide Range

ABSTRACTAchromobacter xylosoxidansis an opportunistic pathogen known to be resistant to a wide range of antibiotics; however, the knowledge about the drug resistance mechanisms is limited. We used a high-throughput sequencing approach to sequence the genomes of theA. xylosoxidanstype strain ATCC 27061 and a clinical isolate,A. xylosoxidansX02736, and then we used different bioinformatics tools to analyze the drug resistance genes in these bacteria. We obtained the complete genome sequence forA. xylosoxidansATCC 27061 and the draft sequence for X02736. We predicted a total of 50 drug resistance-associated genes in the type strain, including 5 genes for β-lactamases and 17 genes for efflux pump systems; these genes are also conserved among otherA. xylosoxidansgenomes. In the clinical isolate, except for the conserved resistance genes, we also identified several acquired resistance genes carried by a new transposon embedded in a novel integrative and conjugative element. Our study provides new insights into the intrinsic and acquired drug resistance mechanisms inA. xylosoxidans, which will be helpful for better understanding the physiology ofA. xylosoxidansand the evolution of antibiotic resistance in this bacterium.

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 Contribution of Genetic Variants of ATP Transporters (ABCC1 and ABCG2) genes with the Pathogenesis of Colorectal Cancer

2018 ◽  
Vol 15 (3) ◽  
pp. 555-559
Author(s):  
Huda A. Al Doghaither ◽  
Ayat B. Al-Ghafari
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Saudi Arabia ◽  
Genetic Variants ◽  
Metastatic Cancer ◽  
Resistance Mechanisms ◽  
Saudi Population ◽  
Chi Square ◽  
Poor Overall Survival ◽  
Acquired Drug Resistance

Colorectal cancer (CRC) is one of the major cancers that is characterized with high percentage of morbidity worldwide due to the advanced metastatic cancer that developed via acquired drug resistance mechanisms. Therefore, there is an urgent need to identify genetic variants in major genes that could contribute to the poor overall survival rate and drug-resistance. ATP-binding cassette (ABC) transporters are among the most studied genes that are related to the development of many cancers including CRC. In this study, three variants namely (G2168A and G3173A) in ABCC1 and (C421A) in ABCG2 were examined to evaluate their contribution to CRC in Saudi Arabia. DNA was extracted from the whole blood of 62 CRC patients and 100 controls. PCR-RFLP technique was used to identify the different genotypes among Saudi population. All statistical data were obtained by chi-square test and P values ˂0.05 were considered statistically significant. Interestingly, neither of the tested variants showed heterozygous nor homozygous distribution among the 162 samples. Therefore, those variants are rare in Saudi population and are not suspected to be involved in CRC pathogenesis. In conclusion, those variants cannot be used as diagnostic or prognostic markers for CRC in Saudi Arabia. However, more experiments need to be performed to confirm our findings.

Genetic and Epigenetic Modulation of Drug Resistance in Cancer: Challenges and Opportunities

2020 ◽  
Vol 20 (14) ◽  
pp. 1114-1131 ◽  
Author(s):  
Kanisha Shah ◽  
Rakesh M. Rawal
Keyword(s):  
Drug Resistance ◽  
Drug Targets ◽  
Complex Disease ◽  
Cancer Therapies ◽  
Altered Expression ◽  
Acquired Drug Resistance ◽  
Challenges And Opportunities ◽  
Chemotherapeutic Treatment ◽  
Epigenetic Modulation ◽  
Targeted Drug Therapies

Cancer is a complex disease that has the ability to develop resistance to traditional therapies. The current chemotherapeutic treatment has become increasingly sophisticated, yet it is not 100% effective against disseminated tumours. Anticancer drugs resistance is an intricate process that ascends from modifications in the drug targets suggesting the need for better targeted therapies in the therapeutic arsenal. Advances in the modern techniques such as DNA microarray, proteomics along with the development of newer targeted drug therapies might provide better strategies to overcome drug resistance. This drug resistance in tumours can be attributed to an individual’s genetic differences, especially in tumoral somatic cells but acquired drug resistance is due to different mechanisms, such as cell death inhibition (apoptosis suppression) altered expression of drug transporters, alteration in drug metabolism epigenetic and drug targets, enhancing DNA repair and gene amplification. This review also focusses on the epigenetic modifications and microRNAs, which induce drug resistance and contributes to the formation of tumour progenitor cells that are not destroyed by conventional cancer therapies. Lastly, this review highlights different means to prevent the formation of drug resistant tumours and provides future directions for better treatment of these resistant tumours.

Clinical applications of circulating tumor DNA in monitoring breast cancer drug resistance

2020 ◽  
Vol 16 (34) ◽  
pp. 2863-2878
Author(s):  
Yang Liu ◽  
Qian Du ◽  
Dan Sun ◽  
Ruiying Han ◽  
Mengmeng Teng ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Clinical Applications ◽  
Current Status ◽  
Cancer Drug ◽  
Genomic Alteration ◽  
Tumor Dna

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. Unfortunately, treatments often fail because of the development of drug resistance, the underlying mechanisms of which remain unclear. Circulating tumor DNA (ctDNA) is free DNA released into the blood by necrosis, apoptosis or direct secretion by tumor cells. In contrast to repeated, highly invasive tumor biopsies, ctDNA reflects all molecular alterations of tumors dynamically and captures both spatial and temporal tumor heterogeneity. Highly sensitive technologies, including personalized digital PCR and deep sequencing, make it possible to monitor response to therapies, predict drug resistance and tailor treatment regimens by identifying the genomic alteration profile of ctDNA, thereby achieving precision medicine. This review focuses on the current status of ctDNA biology, the technologies used to detect ctDNA and the potential clinical applications of identifying drug resistance mechanisms by detecting tumor-specific genomic alterations in breast cancer.

Dissecting the landscape of CAF-mediated drug resistance mechanisms in ALK-rearranged NSCLC

2020 ◽  
Vol 138 ◽  
pp. S48
Author(s):  
Q. Hu ◽  
L.L. Remsing Rix ◽  
X. Li ◽  
E.A. Welsh ◽  
B. Fang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Resistance Mechanisms
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