Nongenetic Mechanisms of Drug Resistance in Melanoma

Resistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.

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Deregulated FASN Expression in BRAF Inhibitor-Resistant Melanoma Cells Unveils New Targets for Drug Combinations

Cancers ◽

10.3390/cancers13092284 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2284

Author(s):

Serena Stamatakos ◽

Giovanni Luca Beretta ◽

Elisabetta Vergani ◽

Matteo Dugo ◽

Cristina Corno ◽

...

Keyword(s):

Drug Resistance ◽

Metastatic Melanoma ◽

Mutant Cell ◽

Braf Inhibitor ◽

Cancer Cell Line ◽

Melanoma Cells ◽

Melanoma Progression ◽

Increased Sensitivity ◽

Resistant Cells

Metabolic changes promoting cell survival are involved in metastatic melanoma progression and in the development of drug resistance. In BRAF-inhibitor resistant melanoma cells, we explored the role of FASN, an enzyme involved in lipogenesis overexpressed in metastatic melanoma. Resistant melanoma cells displaying enhanced migratory and pro-invasive abilities increased sensitivity to the BRAF inhibitor PLX4032 upon the molecular targeting of FASN and upon treatment with the FASN inhibitor orlistat. This behavior was associated with a marked apoptosis and caspase 3/7 activation observed for the drug combination. The expression of FASN was found to be inversely associated with drug resistance in BRAF-mutant cell lines, both in a set of six resistant/sensitive matched lines and in the Cancer Cell Line Encyclopedia. A favorable drug interaction in resistant cells was also observed with U18666 A inhibiting DHCR24, which increased upon FASN targeting. The simultaneous combination of the two inhibitors showed a synergistic interaction with PLX4032 in resistant cells. In conclusion, FASN plays a role in BRAF-mutated melanoma progression, thereby creating novel therapeutic opportunities for the treatment of melanoma.

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Targeting CDC7 sensitizes resistance melanoma cells to BRAFV600E-specific inhibitor by blocking the CDC7/MCM2-7 pathway

Scientific Reports ◽

10.1038/s41598-019-50732-w ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 3

Author(s):

Shaimaa A. Gad ◽

Hamdy E. A. Ali ◽

Rofaida Gaballa ◽

Rania M. Abdelsalam ◽

Mourad Zerfaoui ◽

...

Keyword(s):

Drug Resistance ◽

Metastatic Melanoma ◽

Clinical Effect ◽

Specific Inhibitor ◽

Melanoma Cells ◽

Development Of Resistance ◽

Dual Targeting ◽

Low Concentrations ◽

Resistant Cells

Abstract Although the utilization of selective BRAFV600E inhibitors is associated with improved overall survival in patients with metastatic melanoma, a growing challenge of drug resistance has emerged. CDC7 has been shown to be overexpressed and associated with poor prognosis in various cancers including melanoma. Thus, we aimed to elucidate the biological role of CDC7 in promoting Vemurafenib resistance and the anticipated benefits of dual targeting of BRAFV600E and CDC7 in melanoma cells. We performed exosomes-associated microRNA profiling and functional assays to determine the role of CDC7 in drug resistance using Vemurafenib-sensitive and resistant melanoma cells. Our results demonstrated that Vemurafenib-resistant cells exhibited a persistent expression of CDC7 in addition to prolonged activity of MCM2 compared to drug-sensitive cells. Reconstitution of miR-3613-3p in resistant cells downregulated CDC7 expression and reduced the number of colonies. Treatment of cells with low concentrations of CDC7 inhibitor TAK-931 sensitized resistant cells to Vemurafenib and reduced the number of cell colonies. Taken together, CDC7 overexpression and downregulation of miR-3613-3p were associated with Vemurafenib resistance in BRAFV600E- bearing melanoma cells. Dual targeting of CDC7 and BRAFV600E reduced the development of resistance against Vemurafenib. Further studies are warranted to investigate the clinical effect of targeting CDC7 in metastatic melanoma.

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The future of myeloma precision medicine: integrating the compendium of known drug resistance mechanisms with emerging tumor profiling technologies

Leukemia ◽

10.1038/s41375-018-0362-z ◽

2019 ◽

Vol 33 (4) ◽

pp. 863-883 ◽

Cited By ~ 15

Author(s):

Taylor Harding ◽

Linda Baughn ◽

Shaji Kumar ◽

Brian Van Ness

Keyword(s):

Drug Resistance ◽

Precision Medicine ◽

Resistance Mechanisms ◽

The Future ◽

Tumor Profiling

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Cirsiliol Suppressed Epithelial to Mesenchymal Transition in B16F10 Malignant Melanoma Cells through Alteration of the PI3K/Akt/NF-κB Signaling Pathway

International Journal of Molecular Sciences ◽

10.3390/ijms20030608 ◽

2019 ◽

Vol 20 (3) ◽

pp. 608 ◽

Cited By ~ 7

Author(s):

Priyanka Prasad ◽

Andrea Vasas ◽

Judit Hohmann ◽

Anupam Bishayee ◽

Dona Sinha

Keyword(s):

Malignant Melanoma ◽

Metastatic Melanoma ◽

Signaling Pathway ◽

Metastatic Disease ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Nuclear Factor Κb ◽

Melanoma Cells ◽

Mesenchymal Transition

Malignant melanoma is a highly aggressive form of skin cancer which has a propensity for metastasis. Epithelial mesenchymal transition (EMT) plays a primordial role in the progression of metastatic disease. Metastatic melanoma is resistant to conventional therapies. Hence, researchers have been exploring alternative approaches, including the utility of bioactive phytochemicals to manage metastatic disease. In the present study, we investigated the potential of cirsiliol, a flavonoid isolated from Centaurea jacea L., in modulating the aggressive behavior of B16F10 metastatic melanoma cells, including EMT, and associated molecular mechanisms of action. Cirsiliol was found to be effective in restraining the colony formation and migration of fibronectin-induced B16F10 metastatic melanoma cells. Cirsiliol inhibited the activity and expression of matrix metalloproteinase-9 (MMP-9). Cirsiliol also suppressed the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (also known as Akt)/nuclear factor-κB (NF-κB) signaling pathway which, in turn, caused upregulation of E-cadherin and downregulation of N-cadherin, Snail and Twist. Based on these results, cirsiliol may be considered a promising compound against EMT in the therapeutic management of malignant melanoma.

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ErbB3 Phosphorylation as Central Event in Adaptive Resistance to Targeted Therapy in Metastatic Melanoma: Early Detection in CTCs during Therapy and Insights into Regulation by Autocrine Neuregulin

Cancers ◽

10.3390/cancers11101425 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1425 ◽

Cited By ~ 7

Author(s):

Ciro Francesco Ruggiero ◽

Debora Malpicci ◽

Luigi Fattore ◽

Gabriele Madonna ◽

Vito Vanella ◽

...

Keyword(s):

Drug Resistance ◽

Metastatic Melanoma ◽

Cell Lines ◽

Genetic Resistance ◽

Melanoma Cells ◽

Mek Inhibitors ◽

Adaptive Resistance ◽

Melanoma Patients ◽

Initiation Of Therapy

In recent years the introduction of target therapies with BRAF and MEK inhibitors (MAPKi) and of immunotherapy with anti-CTLA-4 and anti-PD-1 monoclonal antibodies have dramatically improved survival of metastatic melanoma patients. Despite these changes drug resistance remains a major hurdle. Several mechanisms are at the basis of drug resistance. Particular attention has been devoted over the last years to unravel mechanisms at the basis of adaptive/non genetic resistance occurring in BRAF mutated melanomas upon treatment with to MAPKi. In this paper we focus on the involvement of activation of ErbB3 receptor following early exposure of melanoma cells to BRAF or MEK inhibitors, and the following induction of PI3K/AKT pathway. Although different mechanisms have been invoked in the past at the basis of this activation we show here with a combination of approaches that autocrine production of neuregulin by melanoma cells is a major factor responsible for ErbB3 phosphorylation and downstream AKT activation. Interestingly the kinetic of neuregulin production and of the ensuing ErbB3 phosphorylation is different in different melanoma cell lines which underscores the high degree of tumor heterogeneity. Moreover, heterogeneity is further highlighted by the evidence that in different cell lines neuregulin upregulation can occur at the transcriptional or at the post-transcritpional level. Finally we complement our study by showing with a liquid biopsy assay that circulating tumor cells (CTCs) from melanoma patients undergo upregulation of ErbB3 phosphorylation in vivo shortly after initiation of therapy.

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MicroRNAs as Predictive Biomarkers of Resistance to Targeted Therapies in Gastrointestinal Tumors

Biomedicines ◽

10.3390/biomedicines9030318 ◽

2021 ◽

Vol 9 (3) ◽

pp. 318

Author(s):

Valentina Angerilli ◽

Francesca Galuppini ◽

Gianluca Businello ◽

Luca Dal Santo ◽

Edoardo Savarino ◽

...

Keyword(s):

Drug Resistance ◽

Targeted Therapies ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Acquired Resistance ◽

Predictive Biomarkers ◽

Resistance Mechanisms ◽

Specific Gene ◽

Primary Resistance ◽

Ideal Candidate

The advent of precision therapies against specific gene alterations characterizing different neoplasms is revolutionizing the oncology field, opening novel treatment scenarios. However, the onset of resistance mechanisms put in place by the tumor is increasingly emerging, making the use of these drugs ineffective over time. Therefore, the search for indicators that can monitor the development of resistance mechanisms and above all ways to overcome it, is increasingly important. In this scenario, microRNAs are ideal candidate biomarkers, being crucial post-transcriptional regulators of gene expression with a well-known role in mediating mechanisms of drug resistance. Moreover, as microRNAs are stable molecules, easily detectable in tissues and biofluids, they are the ideal candidate biomarker to identify patients with primary resistance to a specific targeted therapy and those who have developed acquired resistance. The aim of this review is to summarize the major studies that have investigated the role of microRNAs as mediators of resistance to targeted therapies currently in use in gastro-intestinal neoplasms, namely anti-EGFR, anti-HER2 and anti-VEGF antibodies, small-molecule tyrosine kinase inhibitors and immune checkpoint inhibitors. For every microRNA and microRNA signature analyzed, the putative mechanisms underlying drug resistance were outlined and the potential to be translated in clinical practice was evaluated.

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The Breast Cancer Stem Cells Traits and Drug Resistance

Frontiers in Pharmacology ◽

10.3389/fphar.2020.599965 ◽

2021 ◽

Vol 11 ◽

Author(s):

Qinghui Zheng ◽

Mengdi Zhang ◽

Fangfang Zhou ◽

Long Zhang ◽

Xuli Meng

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Drug Resistance ◽

Cancer Stem Cells ◽

Drug Efficacy ◽

Resistance Mechanisms ◽

Therapeutic Strategies ◽

Breast Cancer Stem Cells ◽

Drug Resistant ◽

Related Drug

Drug resistance is a major challenge in breast cancer (BC) treatment at present. Accumulating studies indicate that breast cancer stem cells (BCSCs) are responsible for the BC drugs resistance, causing relapse and metastasis in BC patients. Thus, BCSCs elimination could reverse drug resistance and improve drug efficacy to benefit BC patients. Consequently, mastering the knowledge on the proliferation, resistance mechanisms, and separation of BCSCs in BC therapy is extremely helpful for BCSCs-targeted therapeutic strategies. Herein, we summarize the principal BCSCs surface markers and signaling pathways, and list the BCSCs-related drug resistance mechanisms in chemotherapy (CT), endocrine therapy (ET), and targeted therapy (TT), and display therapeutic strategies for targeting BCSCs to reverse drug resistance in BC. Even more importantly, more attention should be paid to studies on BCSC-targeted strategies to overcome the drug resistant dilemma of clinical therapies in the future.

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Adaptive protein and phosphoprotein networks which promote therapeutic sensitivity or acquired resistance

Biochemical Society Transactions ◽

10.1042/bst20140038 ◽

2014 ◽

Vol 42 (4) ◽

pp. 758-764 ◽

Cited By ~ 4

Author(s):

John Haley ◽

Forest M. White

Keyword(s):

Cell Survival ◽

Protein Phosphorylation ◽

Tumour Cell ◽

Targeted Therapies ◽

Tumour Growth ◽

Acquired Resistance ◽

Resistance Mechanisms ◽

Therapeutic Strategies ◽

Therapeutic Resistance ◽

Oncogenic Signalling

Despite the emergence of dozens of oncogenic targets and corresponding molecularly targeted therapies, in most cases tumours continue to progress or recur due to therapeutic resistance. In the present review, we highlight the ability of MS-based phosphoproteomics to quantify oncogenic signalling networks driving tumour growth and invasion, as well as those networks enabling tumour cell survival in the presence of chemotherapeutics. Quantitative protein phosphorylation profiling will facilitate the design and development of optimal therapeutic strategies targeting the initial tumour while simultaneously blocking the predominant resistance mechanisms.

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