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Cancers
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Targeted Therapy of Melanoma: Novel Mechanisms and Biomarkers of Drug...
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Targeted Therapy of Melanoma: Novel Mechanisms and Biomarkers of Drug Resistance

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 10145

Special Issue Editors

Dr. Francesco Facchiano

E-Mail Website
Guest Editor
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Interests: molecular oncology; cell differentiation; biomarker discovery; serum proteomics
Dr. Claudio Tabolacci

E-Mail Website
Guest Editor
Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy
Interests: biochemistry; melanoma cell biology; cancer immunomodulation; phytochemicals
Special Issues, Collections and Topics in MDPI journals
Dr. Stefania D'Atri

E-Mail Website
Guest Editor
Molecular Oncology Laboratory, Istituto Dermopatico dell’Immacolata IDI-IRCCS, 00167 Rome, Italy
Interests: melanoma biology; drug resistance; tumor biomarkers; microRNAs

Special Issue Information

Dear Colleagues, 

Melanoma is an aggressive cutaneous cancer that causes the greatest number of skin-cancer-related deaths worldwide. While early-stage melanoma can be cured successfully by surgical resection, stage IV melanoma has a dismal prognosis and is almost completely resistant to conventional chemotherapy and radiotherapy.

During the last decade, enormous progress has been achieved in the management of metastatic melanoma thanks to the development and introduction in the clinical practice of BRAF and MEK inhibitors and of monoclonal antibodies targeting CTLA-4 and PD-1. However, the percentage of patients presenting primary resistance to therapy, especially to immune checkpoint inhibitors, is still relevant. Furthermore, the development of secondary resistance, especially against inhibitors of BRAF and MEK, limits the long-term efficacy of therapy. Although a variety of molecular mechanisms underlying primary and/or acquired resistance to targeted therapy and immunotherapy have been so far identified, there is still a pressing need to improve our knowledge in this field to identify novel targets and to develop new combinatorial therapeutic approaches aimed at increasing drug sensitivity and overcoming the occurrence of secondary resistance. No less urgent is identifying tumor biomarkers, as predictors of response to therapy or able to detect the emergence of secondary resistance early.

The aim of the present Special Issue is to create a collection of studies focused on the identification of new molecular mechanisms and biomarkers of drug resistance to molecularly targeted drugs used or under investigation to underline the current state of the art in these new promising weapons against cutaneous melanoma.

Dr. Francesco Facchiano
Dr. Claudio Tabolacci
Dr. Stefania D'Atri
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cutaneous melanoma
  • targeted therapy
  • molecular mechanisms of drug resistance
  • new pharmacologic approaches
  • novel tissue and circulating biomarkers

Published Papers (4 papers)

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Research

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22 pages, 3448 KiB  
Article
Increased MARCKS Activity in BRAF Inhibitor-Resistant Melanoma Cells Is Essential for Their Enhanced Metastatic Behavior Independent of Elevated WNT5A and IL-6 Signaling
by Vikas Yadav, Njainday Jobe, Shakti Ranjan Satapathy, Purusottam Mohapatra and Tommy Andersson
Cancers 2022, 14(24), 6077; https://doi.org/10.3390/cancers14246077 - 10 Dec 2022
Cited by 4 | Viewed by 1695
Abstract
Treatment of melanoma with a BRAF inhibitor (BRAFi) frequently initiates development of BRAFi resistance, leading to increased tumor progression and metastasis. Previously, we showed that combined inhibition of elevated WNT5A and IL-6 signaling reduced the invasion and migration of BRAFi-resistant (BRAFi-R) melanoma cells. [...] Read more.
Treatment of melanoma with a BRAF inhibitor (BRAFi) frequently initiates development of BRAFi resistance, leading to increased tumor progression and metastasis. Previously, we showed that combined inhibition of elevated WNT5A and IL-6 signaling reduced the invasion and migration of BRAFi-resistant (BRAFi-R) melanoma cells. However, the use of a combined approach per se and the need for high inhibitor concentrations to achieve this effect indicate a need for an alternative and single target. One such target could be myristoylated alanine-rich C-kinase substrate (MARCKS), a downstream target of WNT5A in BRAFi-sensitive melanoma cells. Our results revealed that MARCKS protein expression and activity are significantly elevated in PLX4032 and PLX4720 BRAFi-R A375 and HTB63 melanoma cells. Surprisingly, neither WNT5A nor IL-6 contributed to the increases in MARCKS expression and activity in BRAFi-R melanoma cells, unlike in BRAFi-sensitive melanoma cells. However, despite the above findings, our functional validation experiments revealed that MARCKS is essential for the increased metastatic behavior of BRAFi-R melanoma cells. Knockdown of MARCKS in BRAFi-R melanoma cells caused reductions in the F-actin content and the number of filopodia-like protrusions, explaining the impaired migration, invasion and metastasis of these cells observed in vitro and in an in vivo zebrafish model. In our search for an alternative explanation for the increased activity of MARCKS in BRAFi-R melanoma cells, we found elevated basal activities of PKCα, PKCε, PKCι, and RhoA. Interestingly, combined inhibition of basal PKC and RhoA effectively impaired MARCKS activity in BRAFi-R melanoma cells. Our results reveal that MARCKS is an attractive single antimetastatic target in BRAFi-R melanoma cells. Full article
(This article belongs to the Special Issue Targeted Therapy of Melanoma: Novel Mechanisms and Biomarkers of Drug Resistance)
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25 pages, 1500 KiB  
Article
Circulating miR-1246 and miR-485-3p as Promising Biomarkers of Clinical Response and Outcome in Melanoma Patients Treated with Targeted Therapy
by Lauretta Levati, Cristian Bassi, Simona Mastroeni, Laura Lupini, Gian Carlo Antonini Cappellini, Laura Bonmassar, Ester Alvino, Simona Caporali, Pedro Miguel Lacal, Maria Grazia Narducci, Ivan Molineris, Federica De Galitiis, Massimo Negrini, Giandomenico Russo and Stefania D’Atri
Cancers 2022, 14(15), 3706; https://doi.org/10.3390/cancers14153706 - 29 Jul 2022
Cited by 4 | Viewed by 1520
Abstract
Despite the significant improvements in advanced melanoma therapy, there is still a pressing need for biomarkers that can predict patient response and prognosis, and therefore support rational treatment decisions. Here, we investigated whether circulating miRNAs could be biomarkers of clinical outcomes in patients [...] Read more.
Despite the significant improvements in advanced melanoma therapy, there is still a pressing need for biomarkers that can predict patient response and prognosis, and therefore support rational treatment decisions. Here, we investigated whether circulating miRNAs could be biomarkers of clinical outcomes in patients treated with targeted therapy. Using next-generation sequencing, we profiled plasma miRNAs at baseline and at progression in patients treated with BRAF inhibitors (BRAFi) or BRAFi + MEKi. Selected miRNAs associated with response to therapy were subjected to validation by real-time quantitative RT-PCR. Receiver Operating Characteristics (ROC), Kaplan–Meier and univariate and multivariate Cox regression analyses were performed on the validated miR-1246 and miR-485-3p baseline levels. The median baseline levels of miR-1246 and miR-485-3p were significantly higher and lower, respectively, in the group of patients not responding to therapy (NRs) as compared with the group of responding patients (Rs). In Rs, a trend toward an increase in miR-1246 and a decrease in miR-485-3p was observed at progression. Baseline miR-1246 level and the miR-1246/miR-485-3p ratio showed a good ability to discriminate between Rs and NRs. Poorer PFS and OS were observed in patients with unfavorable levels of at least one miRNA. In multivariate analysis, a low level of miR-485-3p and a high miR-1246/miR-485-3p ratio remained independent negative prognostic factors for PFS, while a high miR-1246/miR-485-3p ratio was associated with an increased risk of mortality, although statistical significance was not reached. Evaluation of miR-1246 and miR-485-3p baseline plasma levels might help clinicians to identify melanoma patients most likely to be unresponsive to targeted therapy or at higher risk for short-term PFS and mortality, thus improving their management. Full article
(This article belongs to the Special Issue Targeted Therapy of Melanoma: Novel Mechanisms and Biomarkers of Drug Resistance)
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Review

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30 pages, 3068 KiB  
Review
BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers
by Giorgia Castellani, Mariachiara Buccarelli, Maria Beatrice Arasi, Stefania Rossi, Maria Elena Pisanu, Maria Bellenghi, Carla Lintas and Claudio Tabolacci
Cancers 2023, 15(16), 4026; https://doi.org/10.3390/cancers15164026 - 8 Aug 2023
Cited by 10 | Viewed by 2507
Abstract
Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in [...] Read more.
Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs. Full article
(This article belongs to the Special Issue Targeted Therapy of Melanoma: Novel Mechanisms and Biomarkers of Drug Resistance)
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13 pages, 1503 KiB  
Review
BRAF V600-Mutated Metastatic Melanoma and Targeted Therapy Resistance: An Update of the Current Knowledge
by Laetitia Florent, Charles Saby, Florian Slimano and Hamid Morjani
Cancers 2023, 15(9), 2607; https://doi.org/10.3390/cancers15092607 - 4 May 2023
Cited by 6 | Viewed by 3581
Abstract
Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. [...] Read more.
Melanoma is the most common cause of death in skin cancer due to its high metastatic potential. While targeted therapies have improved the care of patients with metastatic melanoma harboring the BRAFV600E mutation, these treatments are associated with a high frequency of resistance. Resistance factors are related to cellular adaptation as well as to changes in the tumor microenvironment. At the cellular level, resistance involves mutations, overexpression, activation, or inhibition of effectors involved in cell signaling pathways such as MAPK, PI3K/AKT, MITF, and epigenetic factors (miRNAs). In addition, several components of the melanoma microenvironment, such as soluble factors, collagen, and stromal cells also play a crucial role in this resistance. In fact, extracellular matrix remodeling impacts the physical and chemical properties with changes in the stiffness and acidity, respectively of the microenvironment. The cellular and immune components of the stroma are also affected, including immune cells and CAF. The aim of this manuscript is to review the mechanisms responsible for resistance to targeted therapies in BRAFV600E-mutated metastatic melanoma. Full article
(This article belongs to the Special Issue Targeted Therapy of Melanoma: Novel Mechanisms and Biomarkers of Drug Resistance)
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