Current Understanding of Drug Resistance Mechanisms and Therapeutic Targets in HER2 Overexpressing Breast Cancers

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.

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

European Journal of Cancer ◽

10.1016/s0959-8049(20)31205-3 ◽

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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Cyclodextrin-Based Hybrid Polymeric Complex to Overcome Dual Drug Resistance Mechanisms for Cancer Therapy

Polymers ◽

10.3390/polym13081254 ◽

2021 ◽

Vol 13 (8) ◽

pp. 1254

Author(s):

Lingjie Ke ◽

Zhiguo Li ◽

Xiaoshan Fan ◽

Xian Jun Loh ◽

Hongwei Cheng ◽

...

Keyword(s):

Drug Resistance ◽

Gene Delivery ◽

Cell Membrane ◽

Inclusion Complex ◽

Polymeric Micelles ◽

Drug Loading ◽

Resistance Mechanisms ◽

Polymeric Complex ◽

Cavity Structure ◽

Dual Drug

Drug resistance always reduces the efficacy of chemotherapy, and the classical mechanisms of drug resistance include drug pump efflux and anti-apoptosis mediators-mediated non-pump resistance. In addition, the amphiphilic polymeric micelles with good biocompatibility and high stability have been proven to deliver the drug molecules inside the cavity into the cell membrane regardless of the efflux of the cell membrane pump. We designed a cyclodextrin (CD)-based polymeric complex to deliver chemotherapeutic doxorubicin (DOX) and Nur77ΔDBD gene for combating pumps and non-pump resistance simultaneously. The natural cavity structure of the polymeric complex, which was comprised with β-cyclodextrin-graft-(poly(ε-caprolactone)-adamantly (β-CD-PCL-AD) and β-cyclodextrin-graft-(poly(ε-caprolactone)-poly(2-(dimethylamino) ethyl methacrylate) (β-CD-PCL-PDMAEMA), can achieve the efficient drug loading and delivery to overcome pump drug resistance. The excellent Nur77ΔDBD gene delivery can reverse Bcl-2 from the tumor protector to killer for inhibiting non-pump resistance. The presence of terminal adamantyl (AD) could insert into the cavity of β-CD-PCL-PDMAEMA via host-guest interaction, and the releasing rate of polymeric inclusion complex was higher than that of the individual β-CD-PCL-PDMAEMA. The polymeric inclusion complex can efficiently deliver the Nur77ΔDBD gene than polyethylenimine (PEI-25k), which is a golden standard for nonviral vector gene delivery. The higher transfection efficacy, rapid DOX cellular uptake, and significant synergetic tumor cell viability inhibition were achieved in a pump and non-pump drug resistance cell model. The combined strategy with dual drug resistance mechanisms holds great potential to combat drug-resistant cancer.

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The Role of Cancer-Associated Fibroblasts in Tumor Progression

Cancers ◽

10.3390/cancers13061399 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1399

Author(s):

Rushikesh S. Joshi ◽

Samanvi S. Kanugula ◽

Sweta Sudhir ◽

Matheus P. Pereira ◽

Saket Jain ◽

...

Keyword(s):

Cancer Treatment ◽

Tumor Progression ◽

Cancer Progression ◽

Immune Cell ◽

Systemic Disease ◽

Genomic Medicine ◽

Therapeutic Targets ◽

Therapy Resistance ◽

Cancer Associated Fibroblasts ◽

Breast Cancers

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

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Drug Resistance in Osteosarcoma: Emerging Biomarkers, Therapeutic Targets and Treatment Strategies

Cancers ◽

10.3390/cancers13122878 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2878

Author(s):

Claudia Maria Hattinger ◽

Maria Pia Patrizio ◽

Leonardo Fantoni ◽

Chiara Casotti ◽

Chiara Riganti ◽

...

Keyword(s):

Drug Resistance ◽

Therapeutic Targets ◽

Treatment Strategies ◽

Cure Rate ◽

Acquired Drug Resistance ◽

Unselected Patient ◽

Dismal Prognosis ◽

Non Coding Rnas ◽

High Grade Osteosarcoma

High-grade osteosarcoma (HGOS), the most common primary malignant tumor of bone, is a highly aggressive neoplasm with a cure rate of approximately 40–50% in unselected patient populations. The major clinical problems opposing the cure of HGOS are the presence of inherent or acquired drug resistance and the development of metastasis. Since the drugs used in first-line chemotherapy protocols for HGOS and clinical outcome have not significantly evolved in the past three decades, there is an urgent need for new therapeutic biomarkers and targeted treatment strategies, which may increase the currently available spectrum of cure modalities. Unresponsive or chemoresistant (refractory) HGOS patients usually encounter a dismal prognosis, mostly because therapeutic options and drugs effective for rescue treatments are scarce. Tailored treatments for different subgroups of HGOS patients stratified according to drug resistance-related biomarkers thus appear as an option that may improve this situation. This review explores drug resistance-related biomarkers, therapeutic targets and new candidate treatment strategies, which have emerged in HGOS. In addition to consolidated biomarkers, specific attention has been paid to the role of non-coding RNAs, tumor-derived extracellular vesicles, and cancer stem cells as contributors to drug resistance in HGOS, in order to highlight new candidate markers and therapeutic targets. The possible use of new non-conventional drugs to overcome the main mechanisms of drug resistance in HGOS are finally discussed.

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Mechanisms of Drug Resistance in the Pathogenesis of Epilepsy: Role of Neuroinflammation. A Literature Review

Brain Sciences ◽

10.3390/brainsci11050663 ◽

2021 ◽

Vol 11 (5) ◽

pp. 663

Author(s):

Elena D. Bazhanova ◽

Alexander A. Kozlov ◽

Anastasia V. Litovchenko

Keyword(s):

Drug Resistance ◽

Premature Death ◽

Resistance Mechanisms ◽

Biomedical Literature ◽

Drug Resistant ◽

Psychological Consequences ◽

Text Documents ◽

Neural Connections ◽

Inflammatory Processes ◽

Drug Resistant Epilepsy

Epilepsy is a chronic neurological disorder characterized by recurring spontaneous seizures. Drug resistance appears in 30% of patients and it can lead to premature death, brain damage or a reduced quality of life. The purpose of the study was to analyze the drug resistance mechanisms, especially neuroinflammation, in the epileptogenesis. The information bases of biomedical literature Scopus, PubMed, Google Scholar and SciVerse were used. To obtain full-text documents, electronic resources of PubMed Central and Research Gate were used. The article examines the recent research of the mechanisms of drug resistance in epilepsy and discusses the hypotheses of drug resistance development (genetic, epigenetic, target hypothesis, etc.). Drug-resistant epilepsy is associated with neuroinflammatory, autoimmune and neurodegenerative processes. Neuroinflammation causes immune, pathophysiological, biochemical and psychological consequences. Focal or systemic unregulated inflammatory processes lead to the formation of aberrant neural connections and hyperexcitable neural networks. Inflammatory mediators affect the endothelium of cerebral vessels, destroy contacts between endothelial cells and induce abnormal angiogenesis (the formation of “leaky” vessels), thereby affecting the blood–brain barrier permeability. Thus, the analysis of pro-inflammatory and other components of epileptogenesis can contribute to the further development of the therapeutic treatment of drug-resistant epilepsy.

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Functional Genomics Approaches to Elucidate Vulnerabilities of Intrinsic and Acquired Chemotherapy Resistance

Cells ◽

10.3390/cells10020260 ◽

2021 ◽

Vol 10 (2) ◽

pp. 260

Author(s):

Ronay Cetin ◽

Eva Quandt ◽

Manuel Kaulich

Keyword(s):

Drug Resistance ◽

Acquired Resistance ◽

Chemotherapy Resistance ◽

Resistance Mechanisms ◽

Therapy Failure ◽

Tightly Coupled ◽

Unbiased Gene ◽

Multiple Drugs ◽

Genome Scale ◽

Gene Perturbations

Drug resistance is a commonly unavoidable consequence of cancer treatment that results in therapy failure and disease relapse. Intrinsic (pre-existing) or acquired resistance mechanisms can be drug-specific or be applicable to multiple drugs, resulting in multidrug resistance. The presence of drug resistance is, however, tightly coupled to changes in cellular homeostasis, which can lead to resistance-coupled vulnerabilities. Unbiased gene perturbations through RNAi and CRISPR technologies are invaluable tools to establish genotype-to-phenotype relationships at the genome scale. Moreover, their application to cancer cell lines can uncover new vulnerabilities that are associated with resistance mechanisms. Here, we discuss targeted and unbiased RNAi and CRISPR efforts in the discovery of drug resistance mechanisms by focusing on first-in-line chemotherapy and their enforced vulnerabilities, and we present a view forward on which measures should be taken to accelerate their clinical translation.

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Coumarin-1,2,3-triazole Hybrid Molecules: An Emerging Scaffold for Combating Drug Resistance

Current Topics in Medicinal Chemistry ◽

10.2174/1568026621666210303145759 ◽

2021 ◽

Vol 21 ◽

Author(s):

Harish C. Upadhyay

Keyword(s):

Drug Resistance ◽

Antimicrobial Agents ◽

Plant Secondary Metabolites ◽

Cost Effective ◽

Resistance Mechanisms ◽

Biologically Active ◽

Multidrug Therapy ◽

Diverse Range ◽

Development Of Resistance ◽

Hybrid Molecules

: No doubt antibiotics have saved billions of lives, but lack of novel antibiotics, development of resistance mechanisms in almost all clinical isolates of bacteria, and recurrent infections caused by persistent bacteria hamper the successful treatment of infections. Due to widespread emergence of resistance, even the new families of antimicrobial agents have a short life expectancy. Drugs acting on single target often lead to drug resistance and are associated with various side effects. To overcome this problem either multidrug therapy or single drug acting on multiple targets may be used. The later are called ‘hybrid molecules’ which are formed by clubbing two biologically active pharmacophores together with or without an appropriate linker. In this rapidly evolving era, the development of natural product-based hybrid molecules may be a super-alternative to multidrug therapy to combat drug resistance caused by various bacterial and fungal strains. Coumarins (benzopyran-2-one) are one of the earliest reported plant secondary metabolites having clinically proven diverse range of pharmacological properties. On the other hand, 1,2,3-triazole is a common pharmacophore in many drugs responsible for polar interactions improving the solubility and binding affinity to biomolecular targets. In this review we discuss recent advances in Coumarin-1,2,3-triazole hybrids as potential antibacterial agents aiming to provide a useful platform for the exploration of new leads with broader spectrum, more effectiveness, less toxicity with multiple modes of action for the development of cost-effective and safer drugs in the future.

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Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

Essays in Biochemistry ◽

10.1042/ebc20180016 ◽

2018 ◽

Vol 62 (4) ◽

pp. 583-593 ◽

Cited By ~ 9

Author(s):

Peter T. Harrison ◽

Paul H. Huang

Keyword(s):

Drug Resistance ◽

Targeted Therapy ◽

Kinase Inhibitors ◽

Effective Means ◽

Deep Understanding ◽

Therapy Resistance ◽

Resistance Mechanisms ◽

Precision Oncology ◽

First Line ◽

Clinical Responses

Drug resistance remains one of the greatest challenges facing precision oncology today. Despite the vast array of resistance mechanisms that cancer cells employ to subvert the effects of targeted therapy, a deep understanding of cancer signalling networks has led to the development of novel strategies to tackle resistance both in the first-line and salvage therapy settings. In this review, we provide a brief overview of the major classes of resistance mechanisms to targeted therapy, including signalling reprogramming and tumour evolution; our discussion also focuses on the use of different forms of polytherapies (such as inhibitor combinations, multi-target kinase inhibitors and HSP90 inhibitors) as a means of combating resistance. The promise and challenges facing each of these polytherapies are elaborated with a perspective on how to effectively deploy such therapies in patients. We highlight efforts to harness computational approaches to predict effective polytherapies and the emerging view that exceptional responders may hold the key to better understanding drug resistance. This review underscores the importance of polytherapies as an effective means of targeting resistance signalling networks and achieving durable clinical responses in the era of personalised cancer medicine.

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Tackling resistance: emerging antimalarials and new parasite targets in the era of elimination

F1000Research ◽

10.12688/f1000research.14874.1 ◽

2018 ◽

Vol 7 ◽

pp. 1170 ◽

Cited By ~ 9

Author(s):

Emily S. Mathews ◽

Audrey R. Odom John

Keyword(s):

Drug Resistance ◽

Malaria Elimination ◽

Large Scale ◽

Therapeutic Targets ◽

Control Measures ◽

Multi Drug Resistance ◽

Development Projects ◽

Combination Therapies ◽

The Past ◽

Antimalarial Compounds

Malaria remains a significant contributor to global human mortality, and roughly half the world’s population is at risk for infection with Plasmodium spp. parasites. Aggressive control measures have reduced the global prevalence of malaria significantly over the past decade. However, resistance to available antimalarials continues to spread, including resistance to the widely used artemisinin-based combination therapies. Novel antimalarial compounds and therapeutic targets are greatly needed. This review will briefly discuss several promising current antimalarial development projects, including artefenomel, ferroquine, cipargamin, SJ733, KAF156, MMV048, and tafenoquine. In addition, we describe recent large-scale genetic and resistance screens that have been instrumental in target discovery. Finally, we highlight new antimalarial targets, which include essential transporters and proteases. These emerging antimalarial compounds and therapeutic targets have the potential to overcome multi-drug resistance in ongoing efforts toward malaria elimination.

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