scholarly journals Rapidly induced drug adaptation mediates escape from BRAF inhibition in single melanoma cells

2020 ◽  
Author(s):  
Chen Yang ◽  
Chengzhe Tian ◽  
Timothy E. Hoffman ◽  
Nicole K. Jacobsen ◽  
Sabrina L. Spencer
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Genetic Factors ◽  
Melanoma Cells ◽  
Drug Action ◽  
Cancer Therapies ◽  
Braf Inhibitors ◽  
Braf Inhibition ◽  
Anti Cancer ◽  
Early Drug

AbstractDespite increasing numbers of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the response of thousands of single melanoma cells to BRAF inhibitors and show that a subset escapes drug within the first 3 days of treatment. Cell-cycle re-entry occurs via a non-genetic mechanism involving activation of mTORC1 and ATF4, validated in cultures of patient biopsies. These escapees cycle periodically in drug, incur significant DNA damage, and out-proliferate non-escapees over extended treatment. Our work reveals a mutagenesis-prone, expanding subpopulation of early drug escapees that may seed development of permanent drug resistance.

scholarly journals Melanoma subpopulations that rapidly escape MAPK pathway inhibition incur DNA damage and rely on stress signalling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Chen Yang ◽  
Chengzhe Tian ◽  
Timothy E. Hoffman ◽  
Nicole K. Jacobsen ◽  
Sabrina L. Spencer
Keyword(s):  
Dna Damage ◽  
Drug Resistance ◽  
Mapk Pathway ◽  
Melanoma Cells ◽  
Cancer Therapies ◽  
Braf Inhibitors ◽  
Anti Cancer ◽  
Genetic Mechanisms ◽  
Pathway Inhibition ◽  
Stress Signalling

AbstractDespite the increasing number of effective anti-cancer therapies, successful treatment is limited by the development of drug resistance. While the contribution of genetic factors to drug resistance is undeniable, little is known about how drug-sensitive cells first evade drug action to proliferate in drug. Here we track the responses of thousands of single melanoma cells to BRAF inhibitors and show that a subset of cells escapes drug via non-genetic mechanisms within the first three days of treatment. Cells that escape drug rely on ATF4 stress signalling to cycle periodically in drug, experience DNA replication defects leading to DNA damage, and yet out-proliferate other cells over extended treatment. Together, our work reveals just how rapidly melanoma cells can adapt to drug treatment, generating a mutagenesis-prone subpopulation that expands over time.

scholarly journals The Role of Cancer Stem Cells in Drug Resistance in Gastroesophageal Junction Adenocarcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Kate Dinneen ◽  
Anne-Marie Baird ◽  
Ciara Ryan ◽  
Orla Sheils
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Current Knowledge ◽  
Gastroesophageal Junction ◽  
Western World ◽  
Specific Cell ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Anti Cancer

Gastroesophageal junction adenocarcinomas (GEJA) have dramatically increased in incidence in the western world since the mid-20th century. Their prognosis is poor, and conventional anti-cancer therapies do not significantly improve survival outcomes. These tumours are comprised of a heterogenous population of both cancer stem cells (CSC) and non-CSCs, with the former playing a crucial role in tumorigenesis, metastasis and importantly drug resistance. Due to the ability of CSCs to self-replicate indefinitely, their resistance to anti-cancer therapies poses a significant barrier to effective treatment of GEJA. Ongoing drug development programmes aim to target and eradicate CSCs, however their characterisation and thus identification is difficult. CSC regulation is complex, involving an array of signalling pathways, which are in turn influenced by a number of entities including epithelial mesenchymal transition (EMT), microRNAs (miRNAs), the tumour microenvironment and epigenetic modifications. Identification of CSCs commonly relies on the expression of specific cell surface markers, yet these markers vary between different malignancies and indeed are often co-expressed in non-neoplastic tissues. Development of targeted drug therapies against CSCs thus requires an understanding of disease-specific CSC markers and regulatory mechanisms. This review details the current knowledge regarding CSCs in GEJA, with particular emphasis on their role in drug resistance.

scholarly journals Regulation of signal transduction pathways in colorectal cancer: implications for therapeutic resistance

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12338
Author(s):  
Yeelon Yeoh ◽  
Teck Yew Low ◽  
Nadiah Abu ◽  
Pey Yee Lee
Keyword(s):  
Colorectal Cancer ◽  
Drug Resistance ◽  
Abc Transporters ◽  
Advanced Colorectal Cancer ◽  
Drug Efflux ◽  
Cancer Therapies ◽  
Cancer Treatments ◽  
Anti Cancer ◽  
Notch Pathways ◽  
Spectrum Of Patients

Resistance to anti-cancer treatments is a critical and widespread health issue that has brought serious impacts on lives, the economy and public policies. Mounting research has suggested that a selected spectrum of patients with advanced colorectal cancer (CRC) tend to respond poorly to both chemotherapeutic and targeted therapeutic regimens. Drug resistance in tumours can occur in an intrinsic or acquired manner, rendering cancer cells insensitive to the treatment of anti-cancer therapies. Multiple factors have been associated with drug resistance. The most well-established factors are the emergence of cancer stem cell-like properties and overexpression of ABC transporters that mediate drug efflux. Besides, there is emerging evidence that signalling pathways that modulate cell survival and drug metabolism play major roles in the maintenance of multidrug resistance in CRC. This article reviews drug resistance in CRC as a result of alterations in the MAPK, PI3K/PKB, Wnt/β-catenin and Notch pathways.

scholarly journals A Triple Co-Delivery Liposomal Carrier That Enhances Apoptosis via an Intrinsic Pathway in Melanoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1982 ◽  
Author(s):  
Nina Filipczak ◽  
Anna Jaromin ◽  
Adriana Piwoni ◽  
Mohamed Mahmud ◽  
Can Sarisozen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Melanoma Cells ◽  
Mitochondrial Pathway ◽  
Cytotoxic Action ◽  
Cancer Therapies ◽  
Normal Cells ◽  
Freeze And Thaw ◽  
Anti Cancer ◽  
Remote Loading ◽  
Activity Mechanism

The effectiveness of existing anti-cancer therapies is based mainly on the stimulation of apoptosis of cancer cells. Most of the existing therapies are somewhat toxic to normal cells. Therefore, the quest for nontoxic, cancer-specific therapies remains. We have demonstrated the ability of liposomes containing anacardic acid, mitoxantrone and ammonium ascorbate to induce the mitochondrial pathway of apoptosis via reactive oxygen species (ROS) production by the killing of cancer cells in monolayer culture and shown its specificity towards melanoma cells. Liposomes were prepared by a lipid hydration, freeze-and-thaw (FAT) procedure and extrusion through polycarbonate filters, a remote loading method was used for dug encapsulation. Following characterization, hemolytic activity, cytotoxicity and apoptosis inducing effects of loaded nanoparticles were investigated. To identify the anticancer activity mechanism of these liposomes, ROS level and caspase 9 activity were measured by fluorescence and by chemiluminescence respectively. We have demonstrated that the developed liposomal formulations produced a high ROS level, enhanced apoptosis and cell death in melanoma cells, but not in normal cells. The proposed mechanism of the cytotoxic action of these liposomes involved specific generation of free radicals by the iron ions mechanism.

scholarly journals The Influence of Tumor Microenvironment on Immune Escape of Melanoma

2020 ◽  
Vol 21 (21) ◽  
pp. 8359 ◽  
Author(s):  
Aleksandra Simiczyjew ◽  
Ewelina Dratkiewicz ◽  
Justyna Mazurkiewicz ◽  
Marcin Ziętek ◽  
Rafał Matkowski ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Immune Escape ◽  
Cell Types ◽  
Melanoma Cells ◽  
Cancer Therapies ◽  
System A ◽  
Anti Cancer ◽  
Low Efficiency ◽  
Inflammatory Molecules

The low efficiency of currently-used anti-cancer therapies poses a serious challenge, especially in the case of malignant melanoma, a cancer characterized by elevated invasiveness and relatively high mortality rate. The role of the tumor microenvironment in the progression of melanoma and its acquisition of resistance to treatment seems to be the main focus of recent studies. One of the factors that, in normal conditions, aids the organism in its fight against the cancer and, following the malignant transformation, adapts to facilitate the development of the tumor is the immune system. A variety of cell types, i.e., T and B lymphocytes, macrophages, and dendritic and natural killer cells, as well as neutrophils, support the growth and invasiveness of melanoma cells, utilizing a plethora of mechanisms, including secretion of pro-inflammatory molecules, induction of inhibitory receptors expression, or depletion of essential nutrients. This review provides a comprehensive summary of the processes regulated by tumor-associated cells that promote the immune escape of melanoma cells. The described mechanisms offer potential new targets for anti-cancer treatment and should be further studied to improve currently-employed therapies.

scholarly journals Molecular Targeting of HuR Oncoprotein Suppresses MITF and Induces Apoptosis in Melanoma Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 166
Author(s):  
Rebaz Ahmed ◽  
Ranganayaki Muralidharan ◽  
Akhil Srivastava ◽  
Sarah E. Johnston ◽  
Yan D. Zhao ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Targeted Therapy ◽  
Antitumor Activity ◽  
Mek Inhibitor ◽  
Melanoma Cells ◽  
Migration And Invasion ◽  
Mutational Status ◽  
The Impact

Background: Treatment of metastatic melanoma possesses challenges due to drug resistance and metastases. Recent advances in targeted therapy and immunotherapy have shown clinical benefits in melanoma patients with increased survival. However, a subset of patients who initially respond to targeted therapy relapse and succumb to the disease. Therefore, efforts to identify new therapeutic targets are underway. Due to its role in stabilizing several oncoproteins’ mRNA, the human antigen R (HuR) has been shown as a promising molecular target for cancer therapy. However, little is known about its potential role in melanoma treatment. Methods: In this study, we tested the impact of siRNA-mediated gene silencing of HuR in human melanoma (MeWo, A375) and normal melanocyte cells in vitro. Cells were treated with HuR siRNA encapsulated in a lipid nanoparticle (NP) either alone or in combination with MEK inhibitor (U0126) and subjected to cell viability, cell-cycle, apoptosis, Western blotting, and cell migration and invasion assays. Cells that were untreated or treated with control siRNA-NP (C-NP) were included as controls. Results: HuR-NP treatment significantly reduced the expression of HuR and HuR-regulated oncoproteins, induced G1 cell cycle arrest, activated apoptosis signaling cascade, and mitigated melanoma cells’ aggressiveness while sparing normal melanocytes. Furthermore, we demonstrated that HuR-NP treatment significantly reduced the expression of the microphthalmia-associated transcription factor (MITF) in both MeWo and MITF-overexpressing MeWo cells (p < 0.05). Finally, combining HuR-NP with U0126 resulted in synergistic antitumor activity against MeWo cells (p < 0.01). Conclusion: HuR-NP exhibited antitumor activity in melanoma cells independent of their oncogenic B-RAF mutational status. Additionally, combinatorial therapy incorporating MEK inhibitor holds promise in overriding MITF-mediated drug resistance in melanoma.

scholarly journals Nek2 Kinase Signaling in Malaria, Bone, Immune and Kidney Disorders to Metastatic Cancers and Drug Resistance: Progress on Nek2 Inhibitor Development

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 347
Author(s):  
Dibyendu Dana ◽  
Tuhin Das ◽  
Athena Choi ◽  
Ashif I. Bhuiyan ◽  
Tirtha K. Das ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Cancer Metastasis ◽  
Kidney Diseases ◽  
Chromosome Instability ◽  
Tumor Development ◽  
Cancer Therapeutics ◽  
Human Diseases ◽  
Cellular Processes ◽  
Anti Cancer

Cell cycle kinases represent an important component of the cell machinery that controls signal transduction involved in cell proliferation, growth, and differentiation. Nek2 is a mitotic Ser/Thr kinase that localizes predominantly to centrosomes and kinetochores and orchestrates centrosome disjunction and faithful chromosomal segregation. Its activity is tightly regulated during the cell cycle with the help of other kinases and phosphatases and via proteasomal degradation. Increased levels of Nek2 kinase can promote centrosome amplification (CA), mitotic defects, chromosome instability (CIN), tumor growth, and cancer metastasis. While it remains a highly attractive target for the development of anti-cancer therapeutics, several new roles of the Nek2 enzyme have recently emerged: these include drug resistance, bone, ciliopathies, immune and kidney diseases, and parasitic diseases such as malaria. Therefore, Nek2 is at the interface of multiple cellular processes and can influence numerous cellular signaling networks. Herein, we provide a critical overview of Nek2 kinase biology and discuss the signaling roles it plays in both normal and diseased human physiology. While the majority of research efforts over the last two decades have focused on the roles of Nek2 kinase in tumor development and cancer metastasis, the signaling mechanisms involving the key players associated with several other notable human diseases are highlighted here. We summarize the efforts made so far to develop Nek2 inhibitory small molecules, illustrate their action modalities, and provide our opinion on the future of Nek2-targeted therapeutics. It is anticipated that the functional inhibition of Nek2 kinase will be a key strategy going forward in drug development, with applications across multiple human diseases.

scholarly journals 654 Cell cycle phase-specific drug resistance as an escape mechanism of melanoma cells

2016 ◽  
Vol 136 (5) ◽  
pp. S116
Author(s):  
K. Beaumont ◽  
D. Hill ◽  
S. Daignault ◽  
D. Sharp ◽  
B. Gabrielli ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Drug Resistance ◽  
Melanoma Cells ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Specific Drug ◽  
Escape Mechanism

scholarly journals Integrated Genomics Identifies miR-181/TFAM Pathway as a Critical Driver of Drug Resistance in Melanoma

2021 ◽  
Vol 22 (4) ◽  
pp. 1801 ◽  
Author(s):  
Anna Barbato ◽  
Antonella Iuliano ◽  
Mariagrazia Volpe ◽  
Romina D’Alterio ◽  
Simona Brillante ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Expression Profiles ◽  
Braf Inhibitor ◽  
Genomic Analysis ◽  
Progression Free Survival ◽  
Melanoma Cells ◽  
Braf Inhibitors ◽  
Development Of Resistance ◽  
Melanoma Patients

MicroRNAs (miRNAs) are attractive therapeutic targets and promising candidates as molecular biomarkers for various therapy-resistant tumors. However, the association between miRNAs and drug resistance in melanoma remains to be elucidated. We used an integrative genomic analysis to comprehensively study the miRNA expression profiles of drug-resistant melanoma patients and cell lines. MicroRNA-181a and -181b (miR181a/b) were identified as the most significantly down-regulated miRNAs in resistant melanoma patients and cell lines. Re-establishment of miR-181a/b expression reverses the resistance of melanoma cells to the BRAF inhibitor dabrafenib. Introduction of miR-181 mimics markedly decreases the expression of TFAM in A375 melanoma cells resistant to BRAF inhibitors. Furthermore, melanoma growth was inhibited in A375 and M14 resistant melanoma cells transfected with miR-181a/b mimics, while miR-181a/b depletion enhanced resistance in sensitive cell lines. Collectively, our study demonstrated that miR-181a/b could reverse the resistance to BRAF inhibitors in dabrafenib resistant melanoma cell lines. In addition, miR-181a and -181b are strongly down-regulated in tumor samples from patients before and after the development of resistance to targeted therapies. Finally, melanoma tissues with high miR-181a and -181b expression presented favorable outcomes in terms of Progression Free Survival, suggesting that miR-181 is a clinically relevant candidate for therapeutic development or biomarker-based therapy selection.

scholarly journals Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Anil Korkut ◽  
Weiqing Wang ◽  
Emek Demir ◽  
Bülent Arman Aksoy ◽  
Xiaohong Jing ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Network Models ◽  
Clinical Problem ◽  
Melanoma Cells ◽  
Drug Combinations ◽  
Protein Kinase Inhibitors ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Important Clinical Problem ◽  
Targeted Cancer Therapies

Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs.

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