scholarly journals Combination therapy targeting the elevated interleukin‐6 level reduces invasive migration of BRAF inhibitor‐resistant melanoma cells

2019 ◽  
Vol 13 (2) ◽  
pp. 480-494 ◽  
Author(s):  
Purusottam Mohapatra ◽  
Chandra Prakash Prasad ◽  
Tommy Andersson
Keyword(s):  
Combination Therapy ◽  
Interleukin 6 ◽  
Braf Inhibitor ◽  
Melanoma Cells

scholarly journals Characterization of Melanoma Cell Lines Resistant to Vemurafenib and Evaluation of Their Responsiveness to EGFR- and MET-Inhibitor Treatment

2019 ◽  
Vol 21 (1) ◽  
pp. 113 ◽  
Author(s):  
Ewelina Dratkiewicz ◽  
Aleksandra Simiczyjew ◽  
Katarzyna Pietraszek-Gremplewicz ◽  
Justyna Mazurkiewicz ◽  
Dorota Nowak
Keyword(s):  
Growth Factor ◽  
Combination Therapy ◽  
Cell Lines ◽  
Growth Factor Receptor ◽  
Specific Inhibitor ◽  
Braf Inhibitor ◽  
Gelatin Zymography ◽  
Melanoma Cells ◽  
Cytotoxicity Test ◽  
Scratch Wound

Constitutively active mutated BRAF kinase occurs in more than 40% of patients suffering from melanoma. To block its activity, a specific inhibitor, vemurafenib, is applied as a therapy. Unfortunately, patients develop resistance to this drug rather quickly. Previously, we demonstrated that pairs of inhibitors directed against EGFR (epidermal growth factor receptor) and MET (hepatocyte growth factor receptor) trigger a synergistic cytotoxic effect in human melanoma cells, and decrease their invasive abilities. In this study, we aimed to generate and characterize melanoma cells resistant to vemurafenib treatment, and then to evaluate the effectiveness of a previously developed therapy in this model. We showed that melanoma cells resistant to the BRAF inhibitor are characterized by a lower proliferation rate and they acquire a spindle-like shape. Using Western Blot, we also noticed increased levels of EGFR, MET, and selected markers of cancer stem cells in generated cell lines. Resistant cells also exhibited increased invasive abilities and elevated proteolytic activity, observed using scratch wound assays and gelatin zymography. Moreover, combination therapy reduced their viability, as measured with a colorimetric cytotoxicity test, and decreased invasiveness. The obtained results validate the application of combination therapy directed against EGFR and MET in melanoma cells resistant to treatment with inhibitors of mutated BRAF.

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

Cancers ◽  
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.

scholarly journals Salutary Response to Targeted Therapy in Anaplastic Thyroid Cancer

2019 ◽  
Vol 7 ◽  
pp. 232470961989094 ◽  
Author(s):  
Sasan Fazeli ◽  
Edina Paal ◽  
Jessica H. Maxwell ◽  
Kenneth D. Burman ◽  
Eric S. Nylen ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Side Effects ◽  
Combination Therapy ◽  
Braf Inhibitor ◽  
Anaplastic Thyroid Cancer ◽  
Mek Inhibitor ◽  
Braf V600e ◽  
Aggressive Tumor ◽  
Well Differentiated

Context. Anaplastic thyroid cancer (ATC) is an aggressive tumor with a median survival of 3 to 9 months, a 1-year survival of less than 10% and without definitive therapies. Recently, in BRAF V600E mutated ATCs, new targeted therapy using a combination of a BRAF inhibitor, dabrafenib (Dab), with a mitogen-activated extracellular protein kinase (MEK) inhibitor, trametinib (Tram), has shown significant promise. Case Description. We report a case of aggressive ATC with 5 sequence mutations: BRAF V600E (mutation fraction [MF] 34%), TERT E441del (MF 37%), RET N579K (MF 55%), EZH2 D154E (MF 60%), and CDK4 S259L (MF 48%). The patient had a dramatic response to the Dab/Tram combination with near complete resolution of his lung, bone, hepatic, and splenic lesions soon after starting therapy. Unfortunately, intolerable side effects (grade 2-3) on this regimen required tapering and discontinuation of the treatment. He had a quick resurgence of disease after stopping the combination therapy. The patient died approximately 3 months after discontinuing Dab/Tram. Autopsy revealed an atrophic thyroid gland with microscopic subcapsular focus of well-differentiated papillary thyroid carcinoma. There was extensive lymphatic spread of the tumor throughout bilateral lungs with fibrosis. No other metastatic site was identified. Conclusion. We report a unique case of ATC with 2 new mutations of EZH2 D154E and CDK S529L. This case exemplifies the significant promise Dab/Tram therapy holds, the potential side effects that limit their use, and autopsy findings status post use of this combination therapy.

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

Oncogene ◽  
2019 ◽  
Vol 39 (7) ◽  
pp. 1466-1483 ◽  
Author(s):  
S. A. Misek ◽  
K. M. Appleton ◽  
T. S. Dexheimer ◽  
E. M. Lisabeth ◽  
R. S. Lo ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Melanoma Cells ◽  
Inhibitor Resistance

scholarly journals The BRAF Inhibitor Vemurafenib Activates Mitochondrial Metabolism and Inhibits Hyperpolarized Pyruvate–Lactate Exchange in BRAF-Mutant Human Melanoma Cells

2016 ◽  
Vol 15 (12) ◽  
pp. 2987-2999 ◽  
Author(s):  
Teresa Delgado-Goni ◽  
Maria Falck Miniotis ◽  
Slawomir Wantuch ◽  
Harold G. Parkes ◽  
Richard Marais ◽  
...  
Keyword(s):  
Braf Inhibitor ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Mitochondrial Metabolism ◽  
Human Melanoma Cells ◽  
Lactate Exchange ◽  
Braf Mutant

scholarly journals CD133 Is Associated with Increased Melanoma Cell Survival after Multikinase Inhibition

2019 ◽  
Vol 2019 ◽  
pp. 1-19 ◽  
Author(s):  
Cynthia M. Simbulan-Rosenthal ◽  
Anirudh Gaur ◽  
Hengbo Zhou ◽  
Maryam AbdusSamad ◽  
Qing Qin ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Kinase Inhibitors ◽  
Braf Inhibitor ◽  
Mek Inhibitor ◽  
Melanoma Cells ◽  
Stem Cell Marker ◽  
High Dose ◽  
Recurrence Rates ◽  
Mapk Inhibitors

FDA-approved kinase inhibitors are now used for melanoma, including combinations of the MEK inhibitor trametinib, and BRAF inhibitor dabrafenib for BRAFV600 mutations. NRAS-mutated cell lines are also sensitive to MEK inhibitionin vitro, and NRAS-mutated tumors have also shown partial response to MEK inhibitors. However, melanoma still has high recurrence rates due to subpopulations, sometimes described as “melanoma initiating cells,” resistant to treatment. Since CD133 is a putative cancer stem cell marker for different cancers, associated with decreased survival, we examined resistance of patient-derived CD133(+) and CD133(-) melanoma cells to MAPK inhibitors. Human melanoma cells were exposed to increasing concentrations of trametinib and/or dabrafenib, either before or after separation into CD133(+) and CD133(-) subpopulations. In parental CD133-mixed lines, the percentages of CD133(+) cells increased significantly (p<0.05) after high-dose drug treatment. Presorted CD133(+) cells also exhibited significantly greater (p<0.05) IC50s for single and combination MAPKI treatment. siRNA knockdown revealed a causal relationship between CD133 and drug resistance. Microarray and qRT-PCR analyses revealed that ten of 18 ABC transporter genes were significantly (P<0.05) upregulated in the CD133(+) subpopulation, while inhibition of ABC activity increased sensitivity, suggesting a mechanism for increased drug resistance of CD133(+) cells.

Targeting signal-transducer-and-activator-of-transcription 3 sensitizes human cutaneous melanoma cells to BRAF inhibitor

2018 ◽  
Vol 23 (1) ◽  
pp. 67-77 ◽  
Author(s):  
Xiaohui Wang ◽  
Huajun Qu ◽  
Yinghe Dong ◽  
Guozhi Wang ◽  
Yuchen Zhen ◽  
...  
Keyword(s):  
Cutaneous Melanoma ◽  
Braf Inhibitor ◽  
Melanoma Cells ◽  
Signal Transducer ◽  
Targeting Signal ◽  
Transcription 3
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