scholarly journals Rho-mediated gene transcription promotes BRAF inhibitor resistance in de-differentiated melanoma cells

2018 ◽  
Author(s):  
SA Misek ◽  
KM Appleton ◽  
TS Dexheimer ◽  
EM Lisabeth ◽  
RS Lo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Gene Transcription ◽  
Melanoma Cell ◽  
Cutaneous Melanoma ◽  
Acquired Resistance ◽  
Rho Kinase ◽  
Braf Inhibitor ◽  
Resistant Cell ◽  
Melanoma Cell Lines

AbstractOver half of cutaneous melanoma tumors have BRAFV600E/Kmutations. Acquired resistance to BRAF inhibitors (BRAFi) remains a major hurdle in attaining durable therapeutic responses. In this study we demonstrate that approximately 50-60% of melanoma cell lines with vemurafenib resistance acquiredin vitroshow activation of RhoA family GTPases. In BRAFi-resistant melanoma cell lines and tumors, activation of RhoA is correlated with decreased expression of melanocyte lineage genes. Using a machine learning approach, we built gene expression-based models to predict drug sensitivity for 265 common anti-cancer compounds. We then projected these signatures onto the collection of TCGA cutaneous melanoma and found that poorly differentiated tumors were predicted to have increased sensitivity to multiple Rho kinase (ROCK) inhibitors. Two transcriptional effectors downstream of Rho, MRTF and YAP1, are activated in the RhoHighBRAFi-resistant cell lines, and resistant cells are more sensitive to inhibition of these transcriptional mechanisms. Taken together, these results support the concept of targeting Rho-regulated gene transcription pathways as a promising therapy approach to restore sensitivity to BRAFi-resistant tumors or as a combination therapy to prevent the onset of drug resistance.

Autophagy inhibitors chloroquine and LY294002 enhance temozolomide cytotoxicity on cutaneous melanoma cell lines in vitro

2017 ◽  
Vol 28 (3) ◽  
pp. 307-315 ◽  
Author(s):  
Oxana O. Ryabaya ◽  
Andrey N. Inshakov ◽  
Angelina V. Egorova ◽  
Marina A. Emelyanova ◽  
Tatiana V. Nasedkina ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Cutaneous Melanoma ◽  
Melanoma Cell Lines

scholarly journals Molecular Alterations Associated with Acquired Drug Resistance during Combined Treatment with Encorafenib and Binimetinib in Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6058
Author(s):  
Vikas Patel ◽  
István Szász ◽  
Viktória Koroknai ◽  
Tímea Kiss ◽  
Margit Balázs
Keyword(s):  
Drug Resistance ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Differentially Expressed ◽  
Molecular Alterations ◽  
Melanoma Cell Lines ◽  
Resistant Cells

Combination treatment using BRAF/MEK inhibitors is a promising therapy for patients with advanced BRAFV600E/K mutant melanoma. However, acquired resistance largely limits the clinical efficacy of this drug combination. Identifying resistance mechanisms is essential to reach long-term, durable responses. During this study, we developed six melanoma cell lines with acquired resistance for BRAFi/MEKi treatment and defined the molecular alterations associated with drug resistance. We observed that the invasion of three resistant cell lines increased significantly compared to the sensitive cells. RNA-sequencing analysis revealed differentially expressed genes that were functionally linked to a variety of biological functions including epithelial-mesenchymal transition, the ROS pathway, and KRAS-signalling. Using proteome profiler array, several differentially expressed proteins were detected, which clustered into a unique pattern. Galectin showed increased expression in four resistant cell lines, being the highest in the WM1617E+BRes cells. We also observed that the resistant cells behaved differently after the withdrawal of the inhibitors, five were not drug addicted at all and did not exhibit significantly increased lethality; however, the viability of one resistant cell line (WM1617E+BRes) decreased significantly. We have selected three resistant cell lines to investigate the protein expression changes after drug withdrawal. The expression patterns of CapG, Enolase 2, and osteopontin were similar in the resistant cells after ten days of “drug holiday”, but the Snail protein was only expressed in the WM1617E+BRes cells, which showed a drug-dependent phenotype, and this might be associated with drug addiction. Our results highlight that melanoma cells use several types of resistance mechanisms involving the altered expression of different proteins to bypass drug treatment.

Abstract B111: Molecular and chemosensitivity profiling of melanoma cell lines with acquired resistance to BRAF inhibitor Vemurafenib.

2013 ◽  
Author(s):  
Rebekka Krumbach ◽  
Anne-Lise Peille ◽  
Torsten Giesemann ◽  
Vincent Vuaroqueaux ◽  
Heiner Fiebig ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Melanoma Cell Lines

Molecular profiling and comparative genomic hybridization analysis in human melanoma cell lines and identification of BRAF amplification in a PLX4032 acquired resistance cell line.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8592-8592
Author(s):  
Erika Maria Von Euw ◽  
Judy Dering ◽  
Lee Anderson ◽  
Charles Ginther ◽  
Hsiao-Wang Cheng ◽  
...  
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Gene Copy ◽  
Comparative Genomic ◽  
Parental Cell Line ◽  
Molecular Heterogeneity ◽  
Melanoma Cell Lines

8592 Background: Melanoma is the most aggressive form of skin cancer. Its management is evolving rapidly due to an improved understanding of the molecular heterogeneity and the development of effective, personalized targeted therapies. PLX4032 is a BRAF inhibitor that induces tumor response in patients with BRAF mutation whose response is limited due to acquired resistance. We used comprehensive microarray and genomic analysis to molecularly characterize a panel of melanoma cell lines with the goal of identifying new molecular subgroups. To better understand the mechanisms of acquired resistance to PLX4032, we included two cell lines that were conditioned in vitro to acquire resistance. Methods: Using microarray, we studied 52 melanoma cell lines for mRNA expression and performed array CGH using genome microarrays. Data analysis was done using Rosetta Resolver and Agilent Analytics 4.0 software. Results: Microarray analysis suggests melanoma is comprised of at least two distinct molecular groups. One group has a differentiated melanocyte phenotype and the other has an expression signature characteristic of progenitor-like cells. The progenitor-like group expresses SOX9, WNT5A and WNT5B and also has the lowest relative expression of MITF. The most differentiated group had the highest MITF and SOX5 levels, while the progenitor-like cell lines have decreased expression. MITF appears to be a strong candidate marker for this group. Positive correlation exists between MITF expression levels and gene copy number, as almost all of the MITF samples amplified by CHG analysis are also overexpressed. A third group shows strong expression of SOX5, SOX10 and Nestin. One of the most important findings is M14-R cell line, conditioned to acquire PLX4032 resistance, has a focal, high level amplification of BRAF (Log2 ratio = 3, 8-fold amplification) when compared with the parental cell line, which is extremely sensitive to PLX4032. Conclusions: These results afford new insight into the potential pathogenesis and classification and provide a greater understanding of melanoma. BRAF amplification could be a novel mechanism of resistance to PLX4032.

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.

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 Expression of cd44 splice variants in human cutaneous melanoma and melanoma cell lines is related to tumor progression and metastatic potential

1995 ◽  
Vol 64 (3) ◽  
pp. 182-188 ◽  
Author(s):  
Eveliene Manten-Horst ◽  
Erik H. J. Danen ◽  
Lia Smit ◽  
Margriet Snoek ◽  
I. Le Caroline Poole ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Cell Lines ◽  
Melanoma Cell ◽  
Cutaneous Melanoma ◽  
Splice Variants ◽  
Metastatic Potential ◽  
Melanoma Cell Lines
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