Combining Mass Spectrometry-Based Phosphoproteomics with a Network-Based Approach to Reveal FLT3-Dependent Mechanisms of Chemoresistance

FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor clinical outcome, relapse and chemotherapeutic resistance. Elucidating the molecular mechanisms underlying FLT3-dependent pathogenesis and drug resistance is a crucial goal of biomedical research. Given the complexity and intricacy of protein signaling networks, deciphering the molecular basis of FLT3-driven drug resistance requires a systems approach. Here we discuss how the recent advances in mass spectrometry (MS)-based (phospho) proteomics and multiparametric analysis accompanied by emerging computational approaches offer a platform to obtain and systematically analyze cell-specific signaling networks and to identify new potential therapeutic targets.

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Mass Spectrometry Untangles Plant Membrane Protein Signaling Networks

Trends in Plant Science ◽

10.1016/j.tplants.2020.03.013 ◽

2020 ◽

Vol 25 (9) ◽

pp. 930-944 ◽

Cited By ~ 1

Author(s):

Yanmei Chen ◽

Wolfram Weckwerth

Keyword(s):

Mass Spectrometry ◽

Membrane Protein ◽

Signaling Networks ◽

Protein Signaling ◽

Protein Signaling Networks

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Quantitative analysis of phosphorylation-based protein signaling networks in the immune system by mass spectrometry

Wiley Interdisciplinary Reviews Systems Biology and Medicine ◽

10.1002/wsbm.123 ◽

2010 ◽

Vol 3 (3) ◽

pp. 368-376 ◽

Cited By ~ 10

Author(s):

Aleksandra Nita-Lazar

Keyword(s):

Mass Spectrometry ◽

Immune System ◽

Quantitative Analysis ◽

Signaling Networks ◽

Protein Signaling ◽

Protein Signaling Networks

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Modeling Protein-Signaling Networks with Granger Causality Test

Frontiers in Computational and Systems Biology - Computational Biology ◽

10.1007/978-1-84996-196-7_13 ◽

2010 ◽

pp. 249-257

Author(s):

Wenqiang Yang ◽

Qiang Luo

Keyword(s):

Granger Causality ◽

Granger Causality Test ◽

Signaling Networks ◽

Protein Signaling ◽

Causality Test ◽

Protein Signaling Networks

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Exploiting evolutionary trade-offs for posttreatment management of drug-resistant populations

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2003132117 ◽

2020 ◽

Vol 117 (30) ◽

pp. 17924-17931

Author(s):

Sergey V. Melnikov ◽

David L. Stevens ◽

Xian Fu ◽

Hui Si Kwok ◽

Jin-Tao Zhang ◽

...

Keyword(s):

Drug Resistance ◽

Molecular Mechanisms ◽

Genetic Alterations ◽

Trna Synthetase ◽

Molecular Defect ◽

Antibiotic Resistant ◽

Resistance Evolution ◽

Growth Defects ◽

Trade Offs ◽

Resistant Cells

Antibiotic resistance frequently evolves through fitness trade-offs in which the genetic alterations that confer resistance to a drug can also cause growth defects in resistant cells. Here, through experimental evolution in a microfluidics-based turbidostat, we demonstrate that antibiotic-resistant cells can be efficiently inhibited by amplifying the fitness costs associated with drug-resistance evolution. Using tavaborole-resistantEscherichia colias a model, we show that genetic mutations in leucyl-tRNA synthetase (that underlie tavaborole resistance) make resistant cells intolerant to norvaline, a chemical analog of leucine that is mistakenly used by tavaborole-resistant cells for protein synthesis. We then show that tavaborole-sensitive cells quickly outcompete tavaborole-resistant cells in the presence of norvaline due to the amplified cost of the molecular defect of tavaborole resistance. This finding illustrates that understanding molecular mechanisms of drug resistance allows us to effectively amplify even small evolutionary vulnerabilities of resistant cells to potentially enhance or enable adaptive therapies by accelerating posttreatment competition between resistant and susceptible cells.

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Multiple Molecular Mechanisms Contribute to a Stepwise Development of Fluconazole Resistance in Clinical Candida albicans Strains

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.12.3065 ◽

1998 ◽

Vol 42 (12) ◽

pp. 3065-3072 ◽

Cited By ~ 229

Author(s):

Renate Franz ◽

Steven L. Kelly ◽

David C. Lamb ◽

Diane E. Kelly ◽

Markus Ruhnke ◽

...

Keyword(s):

Drug Resistance ◽

Candida Albicans ◽

Molecular Mechanisms ◽

Multiple Drug Resistance ◽

Genetic Alterations ◽

Mutant Form ◽

Mrna Levels ◽

Fluconazole Resistance ◽

Stepwise Development ◽

Target Enzyme

ABSTRACT From each of two AIDS patients with oropharyngeal candidiasis, fiveCandida albicans isolates from recurrent episodes of infection which became gradually resistant against fluconazole during antimycotic treatment were analyzed for molecular changes responsible for drug resistance. In both patients, a single C. albicans strain was responsible for the recurrent infections, but the CARE-2 fingerprint pattern of the isolates exhibited minor genetic alterations, indicating that microevolution of the strains took place during fluconazole therapy. In the isolates from patient 1, enhanced mRNA levels of theMDR1 gene, encoding a multiple drug resistance protein from the superfamily of major facilitators, and constitutive high expression of the ERG11 gene, coding for the drug target enzyme sterol 14α-demethylase, correlated with a stepwise development of fluconazole resistance. The resistant strains exhibited reduced accumulation of fluconazole and, for the last in the series, a slight increase in drug needed to inhibit sterol 14α-demethylation in vitro. In the isolates from patient 2, increasedMDR1 mRNA levels and the change from heterozygosity to homozygosity for a mutant form of the ERG11 gene correlated with continuously decreased drug susceptibility. In this series, reduced drug accumulation and increased resistance in the target enzyme activity, sterol 14α-demethylase, were observed. These results demonstrate that different molecular mechanisms contribute to a gradual development of fluconazole resistance in C. albicans.

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Bioactive Compounds from Seaweed with Anti-Leukemic Activity: A Mini-Review on Carotenoids and Phlorotannins

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190311095655 ◽

2020 ◽

Vol 20 (1) ◽

pp. 39-53 ◽

Cited By ~ 1

Author(s):

Tânia P. Almeida ◽

Alice A. Ramos ◽

Joana Ferreira ◽

Amaya Azqueta ◽

Eduardo Rocha

Keyword(s):

Drug Resistance ◽

Bioactive Compounds ◽

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Kinase Inhibitors ◽

First Line ◽

In Vivo Models ◽

Few Data

: Chronic Myeloid Leukemia (CML) represents 15-20% of all new cases of leukemia and is characterized by an uncontrolled proliferation of abnormal myeloid cells. Currently, the first-line of treatment involves Tyrosine Kinase Inhibitors (TKIs), which specifically inhibits the activity of the fusion protein BCR-ABL. However, resistance, mainly due to mutations, can occur. In the attempt to find more effective and less toxic therapies, several approaches are taken into consideration such as research of new anti-leukemic drugs and “combination chemotherapy” where different drugs that act by different mechanisms are used. Here, we reviewed the molecular mechanisms of CML, the main mechanisms of drug resistance and current strategies to enhance the therapeutic effect of TKIs in CML. Despite major advances in CML treatment, new, more potent anticancer drugs and with fewer side effects are needed. Marine organisms, and particularly seaweed, have a high diversity of bioactive compounds with some of them having anticancer activity in several in vitro and in vivo models. The state-of-art suggests that their use during cancer treatment may improve the outcome. We reviewed here the yet few data supporting anti-leukemic activity of some carotenoids and phlorotannins in some leukemia models. Also, strategies to overcome drug resistance are discussed, particularly the combination of conventional drugs with natural compounds.

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Novel Regulatory Mechanisms of Pathogenicity and Virulence to Combat MDR inCandida albicans

International Journal of Microbiology ◽

10.1155/2013/240209 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 12

Author(s):

Saif Hameed ◽

Zeeshan Fatima

Keyword(s):

Drug Resistance ◽

Molecular Mechanisms ◽

Opportunistic Pathogen ◽

Antifungal Drugs ◽

Regulatory Mechanisms ◽

Cross Resistance ◽

Signaling Networks ◽

Antifungal Drug Resistance ◽

Human Fungal Pathogen ◽

Major Factors

Continuous deployment of antifungals in treating infections caused by dimorphic opportunistic pathogenCandida albicanshas led to the emergence of drug resistance resulting in cross-resistance to many unrelated drugs, a phenomenon termed multidrug resistance (MDR). Despite the current understanding of major factors which contribute to MDR mechanisms, there are many lines of evidence suggesting that it is a complex interplay of multiple factors which may be contributed by still unknown mechanisms. Coincidentally with the increased usage of antifungal drugs, the number of reports for antifungal drug resistance has also increased which further highlights the need for understanding novel molecular mechanisms which can be explored to combat MDR, namely, ROS, iron, hypoxia, lipids, morphogenesis, and transcriptional and signaling networks. Considering the worrying evolution of MDR and significance ofC. albicansbeing the most prevalent human fungal pathogen, this review summarizes these new regulatory mechanisms which could be exploited to prevent MDR development inC. albicansas established from recent studies.

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