scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

scholarly journals Inhibition of the Myocardin-Related Transcription Factor pathway increases efficacy of Trametinib in NRAS-mutant melanoma cell lines

2019 ◽  
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Targeted Therapies ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
High Level ◽  
Melanoma Cell Lines

ABSTRACTThe Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (∼50% BRAFV600 mutations and ∼30% NRAS mutations). While targeted therapies have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in NRAS mutant melanomas in part due to their cytostatic effects and primary resistance in this patient population. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. Combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells which have a high level of trametinib resistance. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlights the potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

scholarly journals FGF2 Induces Resistance to Nilotinib through MAPK Pathway Activation in KIT Mutated Melanoma

Cancers ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1062 ◽  
Author(s):  
Pauline Tétu ◽  
Julie Delyon ◽  
Jocelyne André ◽  
Coralie Reger de Moura ◽  
Malak Sabbah ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
De Novo ◽  
Ex Vivo ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
In Situ Data ◽  
Pathway Activation ◽  
Duration Of Response ◽  
Melanoma Cell Lines

KIT is a bona fide oncogene in a subset of melanoma and, ex vivo, KIT inhibitors are very efficient at killing KIT-mutant melanoma cell lines. However, KIT-mutant melanoma tumors tend to show a de novo resistance in most cases and a limited duration of response when response is achieved. We performed pharmacodynamic studies on patients with KIT-mutated melanoma treated with nilotinib, which suggested that the FGF2 axis may be a mechanism of resistance in this subset of melanoma. Using several melanoma cell lines, which are dependent on oncogenic KIT, we showed that although KIT inhibition markedly decreased cell viability in melanoma cell lines with distinct KIT mutations, this effect was lessened in the presence of FGF2 due to inhibition of BIM expression by MAPK pathway activation. Addition of a MEK inhibitor reversed the FGF2-driven resistance for all KIT mutants. We confirmed the expression of FGF2 and activation of MEK-ERK in melanoma patients using in situ data from a clinical trial. Therefore, the combined inhibition of KIT with FGFR or MEK may be a next-step effective clinical strategy in KIT-mutant melanoma.

BIK is involved in BRAF/MEK inhibitor induced apoptosis in melanoma cell lines

2017 ◽  
Vol 404 ◽  
pp. 70-78 ◽  
Author(s):  
Andreas Borst ◽  
Sebastian Haferkamp ◽  
Johannes Grimm ◽  
Manuel Rösch ◽  
Guannan Zhu ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Mek Inhibitor ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

scholarly journals Role of Flavonoids in the Prevention of AhR-Dependent Resistance During Treatment with BRAF Inhibitors

2020 ◽  
Vol 21 (14) ◽  
pp. 5025
Author(s):  
Héloïse M. Leclair ◽  
Nina Tardif ◽  
Anaïs Paris ◽  
Marie-Dominique Galibert ◽  
Sébastien Corre
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Progression Free Survival ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
Melanoma Cell Lines

BRAF and MEK inhibitors (BRAFi and MEKi) are the standard of care for the treatment of metastatic melanoma in patients with BRAFV600E mutations, greatly improving progression-free survival. However, the acquisition of resistance to BRAFi and MEKi remains a difficult clinical challenge, with limited therapeutic options available for these patients. Here, we investigated the therapeutic potential of natural flavonoids as specific AhR (Aryl hydrocarbon Receptor) transcription factor antagonists in combination with BRAFi. Experimental Design: Experiments were performed in vitro and in vivo with various human melanoma cell lines (mutated for BRAFV600E) sensitive or resistant to BRAFi. We evaluated the role of various flavonoids on cell sensitivity to BRAFi and their ability to counteract resistance and the invasive phenotype of melanoma. Results: Flavonoids were highly effective in potentiating BRAFi therapy in human melanoma cell lines by increasing sensitivity and delaying the pool of resistant cells that arise during treatment. As AhR antagonists, flavonoids counteracted a gene expression program associated with the acquisition of resistance and phenotype switching that leads to an invasive and EMT-like phenotype. Conclusions: The use of natural flavonoids opens new therapeutic opportunities for the treatment of patients with BRAF-resistant disease.

In vitro synergy of paclitaxel (Taxol) and vinorelbine (navelbine) against human melanoma cell lines

1997 ◽  
Vol 33 (3) ◽  
pp. 463-470 ◽  
Author(s):  
A. Photiou ◽  
P. Shah ◽  
L.K. Leong ◽  
J. Moss ◽  
S. Retsas
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Human Melanoma ◽  
Human Melanoma Cell ◽  
Melanoma Cell Lines

scholarly journals Identification of Prognostic Biomarker Candidates Associated With Melanoma Using High-Dimensional Genomic Data

2021 ◽  
Vol 12 ◽  
Author(s):  
Brody Kutt ◽  
Rachel Burdorf ◽  
Travaughn Bain ◽  
Nicardo Cameron ◽  
Alexia Pearah ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Response Rates ◽  
Machine Learning Techniques ◽  
High Dimensional ◽  
Small Subset ◽  
Durable Response ◽  
Melanoma Cell Lines

Survival of patients with metastatic melanoma varies widely. Melanoma is a highly proliferative, chemo-resistant disease. With the recent availability of immunotherapies such as checkpoint inhibitors, durable response rates have improved but are often still limited to 2–3 years. Response rates to treatment range from 30 to 45% with combination therapy however no improvement in overall survival is frequently observed. Of the available therapies, many have targeted the BRAFV600E mutation that results in abnormal MAPK pathway activation which is important for regulating cell proliferation. Immune checkpoint inhibitors such as anti-PD-1 and anti-PD-L1 offer better success but response rates are still low. Identifying biomarkers to better target those who will respond and identify the right combination of treatment is the best approach. In this study, we utilize data from the Cancer Cell Line Encyclopedia (CCLE), including 62 samples, to examine features of gene expression (19K+) and copy number (20K+) in the melanoma cell lines. We perform a clustering analysis on the feature set to assess genetically similarity among the cell lines. We then discover which specific genes and combinations thereof maximize cluster density. We design a feature selection approach for high-dimensional datasets that integrates multiple disparate machine learning techniques into one cohesive pipeline. Our approach provides a small subset of genes that can accurately distinguish between the clusters of melanoma cell lines across multiple types of classifiers. In particular, we find only the 15 highest ranked genes among the original 19 K are necessary to achieve perfect or near-perfect test split classification performance. Of these 15 genes, some are known to be linked to melanoma or other cancer progressions, while others have not previously been linked to melanoma and are of interest for further examination.

scholarly journals Atorvastatin enhances the antitumor activity of tamoxifen in B16f10 mouse melanoma cell lines

2020 ◽  
Vol 25 (1) ◽  
pp. 83-91
Author(s):  
Maryam Malek ◽  
◽  
Maedeh Ghasemi ◽  
Golnaz Vaseghi ◽  
Ahmad Ghasemi ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Mevalonate Pathway ◽  
Combined Therapy ◽  
Metastatic Malignant Melanoma ◽  
Mouse Melanoma ◽  
Melanoma Cancer ◽  
Mouse Melanoma Cell ◽  
Melanoma Cell Lines

Introduction: Tamoxifen has been used in the treatment of metastatic malignant melanoma more common with other agents in the combined therapy. Up-regulated activity of the mevalonate pathway has been shown in a range of different cancers. Atorvastatin is the most commonly used statin approved for cholesterol reduction by inhibiting the mevalonate pathway and has been shown to inhibit tumor growth. In the present study, we used atorvastatin and tamoxifen combination therapy on B16f10 mouse melanoma cell lines to study whether atorvastatin could increase the sensitivity of melanoma cells to the chemotherapeutic agent such as tamoxifen. Methods: The cell line was treated with different concentrations of tamoxifen and/or atorvastatin for 24 and 48h and the effects of treatment on p53 and RhoA were investigated using quantitative RT-PCR. Results: The combination of atorvastatin and tamoxifen resulted in a potentiation antitumor effect via up-regulation of p53 and down-regulation of RhoA expression against melanoma tumors in vitro. Furthermore, we demonstrated the combination of atorvastatin with tamoxifen could reduce tamoxifen dose to minimize possible detrimental side effects in melanoma. Conclusion: Our results suggested that atorvastatin as a combined therapy with tamoxifen may provide a new approach for improving the efficacy and treating against melanoma cancer but needs further exploration in clinical trials.

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