scholarly journals Autocrine Signaling of NRP1 Ligand Galectin-1 Elicits Resistance to BRAF-Targeted Therapy in Melanoma Cells

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2218
Author(s):  
Sabrina Rizzolio ◽  
Simona Corso ◽  
Silvia Giordano ◽  
Luca Tamagnone
Keyword(s):  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Combined Treatment ◽  
Melanoma Cells ◽  
Drug Resistant ◽  
Braf Inhibitors ◽  
Autocrine Signaling ◽  
Melanoma Tumor ◽  
Neuropilin 1 ◽  
Soluble Ligand

Melanoma cells addicted to mutated BRAF oncogene activity can be targeted by specific kinase inhibitors until they develop resistance to therapy. We observed that the expression of Galectin-1 (Gal-1), a soluble ligand of Neuropilin-1 (NRP1), is upregulated in melanoma tumor samples and melanoma cells resistant to BRAF-targeted therapy. We then demonstrated that Gal-1 is a novel driver of resistance to BRAF inhibitors in melanoma and that its activity is linked to the concomitant upregulation of the NRP1 receptor observed in drug-resistant cells. Mechanistically, Gal-1 sustains increased expression of NRP1 and EGFR in drug-resistant melanoma cells. Moreover, consistent with its role as a NRP1 ligand, Gal-1 negatively controls p27 levels, a mechanism previously found to enable EGFR upregulation in cancer cells. Finally, the combined treatment with a Gal-1 inhibitor and a NRP1 blocking drug enabled resistant melanoma cell resensitization to BRAF-targeted therapy. In summary, we found that the activation of Galectin-1/NRP1 autocrine signaling is a new mechanism conferring independence from BRAF kinase activity to oncogene-addicted melanoma cells.

scholarly journals NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma

2020 ◽  
Vol 14 (1) ◽  
pp. 23
Author(s):  
Zili Zhai ◽  
Prasanna K. Vaddi ◽  
Jenny Mae Samson ◽  
Tomoya Takegami ◽  
Mayumi Fujita
Keyword(s):  
Targeted Therapy ◽  
Protein Kinase ◽  
Metastatic Melanoma ◽  
Therapy Resistance ◽  
Melanoma Cells ◽  
Erk Signaling ◽  
Erk Pathway ◽  
Drug Resistant ◽  
Downstream Effector ◽  
Resistant Cells

The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and its downstream effector responses. Uncovering the hidden downstream effectors can aid in understanding melanoma biology and improve targeted therapy efficacy. The inflammasome sensor, NACHT, LRR, and PYD domains-containing protein 1 (NLRP1), is responsible for IL-1β maturation and itself is a melanoma tumor promoter. Here, we report that NLRP1 is a downstream effector of MAPK/ERK signaling through the activating transcription factor 4 (ATF4), creating regulation in metastatic melanoma cells. We confirmed that the NLRP1 gene is a target of ATF4. Interestingly, ATF4/NLRP1 regulation by the MAPK/ERK pathway uses distinct mechanisms in melanoma cells before and after the acquired resistance to targeted therapy. In parental cells, ATF4/NLRP1 is regulated by the MAPK/ERK pathway through the ribosomal S6 kinase 2 (RSK2). However, vemurafenib (VEM) and trametinib (TRA)-resistant cells lose the signaling via RSK2 and activate the cAMP/protein kinase A (PKA) pathway to redirect ATF4/NLRP1. Therefore, NLRP1 expression and IL-1β secretion were downregulated in response to VEM and TRA in parental cells but enhanced in drug-resistant cells. Lastly, silencing NLRP1 in drug-resistant cells reduced their cell growth and inhibited colony formation. In summary, we demonstrated that NLRP1 functions downstream of the MAPK/ERK signaling via ATF4 and is a player of targeted therapy resistance in melanoma. Targeting NLRP1 may improve the therapeutic efficacy of targeted therapy in melanoma.

Adipocytes Contribute to Resistance of Human Melanoma Cells to Chemotherapy and Targeted Therapy

2014 ◽  
Vol 21 (10) ◽  
pp. 1255-1267 ◽  
Author(s):  
M. Chi ◽  
J. Chen ◽  
Y. Ye ◽  
Hsin-Yi Tseng ◽  
F. Lai ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Melanoma Cells ◽  
Human Melanoma ◽  
Human Melanoma Cells

Ethanolic Extract of Algerian Propolis and Galangin Decreased Murine Melanoma Tumor Progression in Mice

2016 ◽  
Vol 16 (9) ◽  
pp. 1172-1183 ◽  
Author(s):  
Lamia Benguedouar ◽  
Mesbah Lahouel ◽  
Sophie C. Gangloff ◽  
Anne Durlach ◽  
Florent Grange ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Tumour Progression ◽  
Ethanolic Extract ◽  
Complementary Therapy ◽  
Melanoma Cells ◽  
Biological Properties ◽  
Therapeutic Treatment ◽  
Melanoma Tumor ◽  
Ki 67

Melanoma is the more dangerous skin cancer, and metastatic melanoma still carries poor prognosis. Despite recent therapeutic advances, prolonged survival remains rare and research is still required. Propolis extracts from many countries have attracted a great deal of attention for their biological properties. We here investigated the ability of an ethanolic extract of Algerian propolis (EEP) to control melanoma tumour growth when given to mice bearing B16F1melanoma tumour either as preventive or as therapeutic treatment. EEP given after tumour occurrence increased mice survival (+30%) and reduced tumour growth (-75%). This was associated with a decrease of the Mitotic Index (-75%) and of Ki-67 (-50%) expression. When given either before or both before and after tumour occurrence, EEP reduced tumour growth but without prolonging mice life. Isolation of B16F1 melanoma cells from resected tumour showed that preventive and curative EEP treatments reduced invasiveness by 55% and 40% respectively compared to control. Galangin, one of the most abundant flavonoids in propolis, significantly reduced the number of melanoma cells in vitro and induced autophagy/apoptosis dose dependently. In conclusion, we showed that EEP reduced melanoma tumour progression/dissemination and could extend mice lifespan when used as therapeutic treatment. Then, EEP may help patients with melanoma when used as a complementary therapy to classical treatment for which autophagy is not contraindicated.

scholarly journals Computational evaluation of potent 2-(1H-imidazol-2-yl) pyridine derivatives as potential V600E-BRAF inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Abdullahi Bello Umar ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Docking Studies ◽  
Major Protein ◽  
Pharmacological Properties ◽  
Braf Inhibitors ◽  
Protein Target ◽  
Computational Evaluation ◽  
Better Than

Abstract Background V600E-BRAF is a major protein target involved in various types of human cancers. However, the acquired resistance of the V600E-BRAF kinase to the vemurafenib and the side effects of other identified drugs initiate the search for efficient inhibitors. In the current paper, virtual docking screening combined with drug likeness and ADMET properties predictions were jointly applied to evaluate potent 2-(1H-imidazol-2-yl) pyridines as V600E-BRAF kinase inhibitors. Results Most of the studied compounds showed better docking scores and favorable interactions with theiV600E-BRAF target. Among the screened compounds, the two most potent (14 and 30) with good rerank scores (−124.079 and − 122.290) emerged as the most effective, and potent V600E-BRAF kinase inhibitors which performed better than vemurafenib (−116.174), an approved V600E-BRAF kinase inhibitor. Thus, the docking studies exhibited that these compounds have shown competing inhibition of V600E-BRAF kinase with vemurafenib at the active site and revealed better pharmacological properties based on Lipinski’s and Veber’s drug-likeness rules for oral bioavailability and ADMET properties. Conclusion The docking result, drug-likeness rules, and ADMET parameters identified compounds (14 and 30) as the best hits against V600E-BRAF kinase with better pharmacological properties. This suggests that these compounds may be developed as potent V600E-BRAF inhibitors.

scholarly journals Typing FGFR2 translocation determines the response to targeted therapy of intrahepatic cholangiocarcinomas

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Xiaohong Pu ◽  
Qing Ye ◽  
Jing Cai ◽  
Xin Yang ◽  
Yao Fu ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Bile Duct ◽  
Kinase Inhibitors ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Chromosomal Translocations ◽  
Small Bile Duct ◽  
Druggable Targets ◽  
Inhibitor Treatment ◽  
Specific Inhibitors

AbstractChromosomal translocations involving fibroblast growth factor receptor 2 (FGFR2) gene at the breakpoints are common genetic lesions in intrahepatic cholangiocarcinoma (ICC) and the resultant fusion protein products have emerged as promising druggable targets. However, predicting the sensitivity of FGFR2 fusions to FGFR kinase inhibitors is crucial to the prognosis of the ICC-targeted therapy. Here, we report identification of nine FGFR2 translocations out of 173 (5.2%) ICC tumors. Although clinicopathologically these FGFR2 translocation bearing ICC tumors are indistinguishable from the rest of the cohort, they are invariably of the mass-forming type originated from the small bile duct. We show that the protein products of FGFR2 fusions can be classified into three subtypes based on the breaking positions of the fusion partners: the classical fusions that retain the tyrosine kinase (TK) and the Immunoglobulin (Ig)-like domains (n = 6); the sub-classical fusions that retain only the TK domain without the Ig-like domain (n = 1); and the non-classical fusions that lack both the TK and Ig-like domains (n = 2). We demonstrate that cholangiocarcinoma cells engineered to express the classical and sub-classical fusions show sensitivity to FGFR-specific kinase inhibitors as evident by the suppression of MAPK/ERK and AKT/PI3K activities following the inhibitor treatment. Furthermore, the kinase-deficient mutant of the sub-classical fusion also lost its sensitivity to the FGFR-specific inhibitors. Taken together, our study suggests that it is essential to determine the breakpoint and type of FGFR2 fusions in the small bile duct subtype of ICC for the targeted treatment.

scholarly journals Long noncoding RNA LINC01291 promotes the aggressive properties of melanoma by functioning as a competing endogenous RNA for microRNA-625-5p and subsequently increasing IGF-1R expression

2021 ◽  
Author(s):  
Lijun Wu ◽  
Ke Li ◽  
Wei Lin ◽  
Jianjiang Liu ◽  
Qiang Qi ◽  
...  
Keyword(s):  
Colony Formation ◽  
Noncoding Rna ◽  
Melanoma Cells ◽  
The Cancer Genome Atlas ◽  
Cell Counting ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Competing Endogenous Rna ◽  
Melanoma Tumor

AbstractStudies have confirmed the relationship between dysregulated long noncoding RNAs and melanoma pathogenesis. However, the regulatory functions of long intergenic non-protein coding RNA 1291 (LINC01291) in melanoma remain unknown. Therefore, we evaluated LINC01291 expression in melanoma and explored its roles in regulating tumor behaviors. Further, the molecular events via which LINC01291 affects melanoma cells were investigated. LINC01291 expression in melanoma cells was analyzed using The Cancer Genome Atlas database and quantitative real-time polymerase chain reaction. Functional assays, including the Cell Counting Kit-8 assay, colony formation assay, flow cytometry, cell migration and invasion assays, and tumor xenograft models, were used to examine LINC01291’s role in melanoma cells. Additionally, bioinformatics analysis, RNA immunoprecipitation, luciferase reporter assay, and western blotting were conducted to determine the tumor-promoting mechanism of LINC01291. LINC01291 was upregulated in melanoma tissues and cell lines. Following LINC01291 knockdown, cell proliferation, colony formation, migration, and invasion were diminished, whereas apoptosis was enhanced and the cell cycle was arrested at G0/G1. In addition, loss of LINC01291 decreased the chemoresistance of melanoma cells to cisplatin. Furthermore, LINC01291 interference inhibited melanoma tumor growth in vivo. Mechanistically, LINC01291 functions as a competing endogenous RNA by sponging microRNA-625-5p (miR-625-5p) in melanoma cells and maintaining insulin-like growth factor 1 receptor (IGF-1R) expression. Rescue experiments revealed that the roles induced by LINC01291 depletion in melanoma cells could be reversed by suppressing miR-625-5p or overexpressing IGF-1R. Our study identified the LINC01291/miR-625-5p/IGF-1R competing endogenous RNA pathway in melanoma cells, which may represent a novel diagnostic biomarker and an effective therapeutic target for melanoma.

scholarly journals Drugs Associated With the Development of Palmoplantar Keratoderma: A Systematic Review

2021 ◽  
pp. 120347542110045
Author(s):  
Sara Mirali ◽  
Abrahim Abduelmula ◽  
Asfandyar Mufti ◽  
Muskaan Sachdeva ◽  
Jensen Yeung
Keyword(s):  
Systematic Review ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Complete Resolution ◽  
Kinase Inhibitors ◽  
Healthcare Providers ◽  
Latency Period ◽  
Braf Inhibitors ◽  
Palmoplantar Keratoderma ◽  
Drug Induced

Background Palmoplantar keratoderma (PPK) are a heterogenous group of hereditary and acquired disorders that are characterized by excessive epidermal thickening of the palms and/or soles. PPK has been described as a rare adverse event for some medications. The aim of this systematic review was to summarize outcomes in PPK associated with various medications. This data will assist dermatologists and other healthcare providers treating patients with drug-induced PPK. Methods EMBASE and MEDLINE databases were searched in accordance with PRISMA guidelines using the keyword “palmoplantar keratoderma.” 40 studies met the inclusion criteria. Results A total of 247 patients (mean age: 57.0 years) were included in the analysis. Among patients whose sex was reported, 60.3% ( n = 35/58) were male. PPK most frequently developed after treatment with BRAF inhibitors (73.7%, n = 182/247), BRAF inhibitors combined with MEK1/2 inhibitors (15.4%, n = 38/247), tyrosine kinase inhibitors (TKIs) (3.2%, n = 8/247), or chemotherapy (2.4%, n = 6/247). The mean latency period between initiation of the drug and onset of PPK was 7.6 months (range: 0.25-90 months). Improvement of PPK was reported in 24 cases, with 50% ( n = 12/24) achieving complete resolution and 50% ( n = 12/24) achieving partial resolution. All patients who achieved complete resolution stopped the suspected drug, with a mean resolution period of 2.4 months (range: 2 weeks-6 months). The most common treatments for PPK were keratolytic treatments ( n = 10) and topical corticosteroids ( n = 4). Conclusions PPK was most frequently associated with targeted kinase inhibitors, specifically BRAF, MEK1/2, and tyrosine kinase inhibitors.

scholarly journals EXTH-16. TREATMENT OF THREE DIFFERENT BRAF-V600E POSITIVE BRAIN TUMORS WITH VEMURAFENIB AND DABRAFENIB/TRAMETINIB: A CASE SERIES

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii90-ii90
Author(s):  
Nikita Dhir ◽  
Sheila Chandrahas ◽  
Chibuzo O’Suoji ◽  
Mohamad Al-Rahawan
Keyword(s):  
Targeted Therapy ◽  
Brain Tumors ◽  
Tumor Regression ◽  
Case Series ◽  
Pediatric Brain Tumors ◽  
Braf V600e ◽  
Cns Tumors ◽  
Braf Inhibitors ◽  
Pediatric Brain ◽  
Pediatric Cns Tumors

Abstract BACKGROUND The BRAF-V600E gene is a protein kinase involved in regulation of the mitogen activated protein kinase pathway (MAPK/MEK) and downstream extracellular receptor kinase (ERK). The BRAF-V600E mutation has a significant role in the progression of pediatric brain tumors. 85% of pediatric CNS tumors express the BRAF mutation. Thus, BRAF targeted therapy in pediatric CNS malignancies has potential to become the standard of care for tumors expressing this mutation. OBJECTIVE Current pediatric CNS brain tumor treatment focuses on chemotherapy and radiation, causing significant toxic side effects for patients. The significance of this case series lies in relaying our experience using targeted therapy in BRAF-V600E positive CNS pediatric brain tumors. METHODS We followed the disease course, progression, and treatment of three pediatric patients with three different CNS tumors. Each of these individuals was treated with surgical resection, chemotherapy, and/or radiation as per standard protocol. When that modality failed to reduce tumor progression, we found that each of their different tumors was BRAF-V600E positive and they were all started on targeted therapy. DISCUSSION Vemurafenib, Dabrafenib, and Trametinib are BRAF-V600E/MEK inhibitors that were initially used to treat melanomas. However, more research has shown that various pediatric CNS tumors are BRAF-V600 positive. Therapy with these BRAF inhibitors has been shown to slow tumor progression, but toxicity can be severe. This case series shows one patient with successful tumor regression, one patient with prolonged disease stabilization, and one patient with initial response but subsequent progression and ultimate death. It has been shown that using BRAF inhibitors in lower grade CNS tumors are more effective than higher grade CNS tumors. CONCLUSION The success of Vemurafenib and Dabrafenib/Trametinib in causing pediatric CNS tumor regression is promising, but further studies are needed to solidify their role in pediatric CNS cancers.

Combined Treatment of Adriamycin and Dipyridamole Inhibits Lung Metastasis of B16 Melanoma Cells in Mice

1990 ◽  
Vol 22 (4) ◽  
pp. 213-218 ◽  
Author(s):  
Y. Sakaguchi ◽  
Y. Emi ◽  
Y. Maehara ◽  
S. Kohnoe ◽  
K. Sugimachi
Keyword(s):  
Lung Metastasis ◽  
Combined Treatment ◽  
Melanoma Cells ◽  
B16 Melanoma ◽  
B16 Melanoma Cells

scholarly journals Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

2018 ◽  
Vol 62 (4) ◽  
pp. 583-593 ◽  
Author(s):  
Peter T. Harrison ◽  
Paul H. Huang
Keyword(s):  
Drug Resistance ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Effective Means ◽  
Deep Understanding ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Precision Oncology ◽  
First Line ◽  
Clinical Responses

Drug resistance remains one of the greatest challenges facing precision oncology today. Despite the vast array of resistance mechanisms that cancer cells employ to subvert the effects of targeted therapy, a deep understanding of cancer signalling networks has led to the development of novel strategies to tackle resistance both in the first-line and salvage therapy settings. In this review, we provide a brief overview of the major classes of resistance mechanisms to targeted therapy, including signalling reprogramming and tumour evolution; our discussion also focuses on the use of different forms of polytherapies (such as inhibitor combinations, multi-target kinase inhibitors and HSP90 inhibitors) as a means of combating resistance. The promise and challenges facing each of these polytherapies are elaborated with a perspective on how to effectively deploy such therapies in patients. We highlight efforts to harness computational approaches to predict effective polytherapies and the emerging view that exceptional responders may hold the key to better understanding drug resistance. This review underscores the importance of polytherapies as an effective means of targeting resistance signalling networks and achieving durable clinical responses in the era of personalised cancer medicine.

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