scholarly journals Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Bilgen Gençler ◽  
Müzeyyen Gönül
Keyword(s):  
Side Effects ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Case Reports ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Cutaneous Side Effects ◽  
Downstream Signaling

The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.

scholarly journals BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition

2018 ◽  
pp. 1-14 ◽  
Author(s):  
Tania Moujaber ◽  
Dariush Etemadmoghadam ◽  
Catherine J. Kennedy ◽  
Yoke-Eng Chiew ◽  
Rosemary L. Balleine ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Targeted Treatment ◽  
Ca 125 ◽  
Low Grade ◽  
Tumor Type ◽  
Braf Inhibitors ◽  
Braf Mutations

Purpose Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma–mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Patients and Methods Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Results Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation–positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. Conclusion BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.

Treatment of a BRAF V600E Positive Ameloblastoma in a Pediatric Patient with MEK Inhibitor Monotherapy

FACE ◽  
2021 ◽  
pp. 273250162110051
Author(s):  
Steven Daws ◽  
Kongkrit Chaiyasate ◽  
Arshi Lehal
Keyword(s):  
Mapk Pathway ◽  
Case Reports ◽  
Radical Resection ◽  
Mek Inhibitor ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Targeted Chemotherapy ◽  
Odontogenic Epithelium ◽  
Genetic Landscape ◽  
Frequent Presence

Ameloblastomas are uncommon tumors of the odontogenic epithelium standardly treated with radical resection. Recent studies of the genetic landscape of ameloblastoma have revealed the frequent presence of the BRAF V600E mutation, suggesting a possible role for targeted chemotherapy. We present the case of a primary mandibular ameloblastoma found in a 13-year-old female with confirmed BRAF V600E mutation. Prior to invasive surgical intervention she was treated for 8 weeks with the MEK inhibitor trametinib, but her tumor demonstrated little radiographic, clinical, or histologic response. Previous case reports have shown ameloblastoma in adult patients to be responsive to other agents targeting the MAPK pathway. Our observations in the presented case demonstrate the need for further research into the utility of targeted chemotherapy in ameloblastoma treatment.

scholarly journals Oxidative Stress-Related Mechanisms in Melanoma and in the Acquired Resistance to Targeted Therapies

Antioxidants ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 1942
Author(s):  
Stefania Pizzimenti ◽  
Simone Ribero ◽  
Marie Angele Cucci ◽  
Margherita Grattarola ◽  
Chiara Monge ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Targeted Therapies ◽  
Current Knowledge ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Advanced Melanoma ◽  
Braf Mutations ◽  
Downstream Signaling ◽  
Activating Mutations

Melanoma is a highly aggressive cancer with the poorest prognosis, representing the deadliest form of skin cancer. Activating mutations in BRAF are the most frequent genetic alterations, present in approximately 50% of all melanoma cases. The use of specific inhibitors towards mutant BRAF variants and MEK, a downstream signaling target of BRAF in the MAPK pathway, has significantly improved progression-free and overall survival in advanced melanoma patients carrying BRAF mutations. Nevertheless, despite these improvements, resistance still develops within the first year of therapy in around 50% of patients, which is a significant problem in managing BRAF-mutated advanced melanoma. Understanding these mechanisms is one of the mainstreams of the research on BRAFi/MEKi acquired resistance. Both genetic and epigenetic mechanisms have been described. Moreover, in recent years, oxidative stress has emerged as another major force involved in all the phases of melanoma development, from initiation to progression until the onsets of the metastatic phenotype and chemoresistance, and has thus become a target for therapy. In the present review, we discuss the current knowledge on oxidative stress and its signaling in melanoma, as well as the oxidative stress-related mechanisms in the acquired resistance to targeted therapies.

Polymorphous Low-Grade Neuroepithelial Tumor of the Young (PLNTY): Molecular Profiling Confirms Frequent MAPK Pathway Activation

2021 ◽  
Author(s):  
Cristiane M Ida ◽  
Derek R Johnson ◽  
Asha A Nair ◽  
Jaime Davila ◽  
Thomas M Kollmeyer ◽  
...  
Keyword(s):  
Copy Number ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Low Grade ◽  
Pathway Activation ◽  
Mitogen Activated Protein ◽  
Copy Number Changes ◽  
Cd34 Expression

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and frequent mitogen-activated protein kinase (MAPK) pathway activation. We molecularly profiled 13 cases with diagnostic histopathological features of PLNTY (10 female; median age, 16 years; range, 5–52). Patients frequently presented with seizures (9 of 12 with available history) and temporal lobe tumors (9 of 13). MAPK pathway activating alterations were identified in all 13 cases. Fusions were present in the 7 youngest patients: FGFR2-CTNNA3 (n = 2), FGFR2-KIAA1598 (FGFR2-SHTN1) (n = 1), FGFR2-INA (n = 1), FGFR2-MPRIP (n = 1), QKI-NTRK2 (n = 1), and KIAA1549-BRAF (n = 1). BRAF V600E mutation was present in 6 patients (17 years or older). Two fusion-positive cases additionally harbored TP53/RB1 abnormalities suggesting biallelic inactivation. Copy number changes predominantly involving whole chromosomes were observed in all 10 evaluated cases, with losses of chromosome 10q occurring with FGFR2-KIAA1598 (SHTN1)/CTNNA3 fusions. The KIAA1549-BRAF and QKI-NTRK2 fusions were associated respectively with a 7q34 deletion and 9q21 duplication. This study shows that despite its name, PLNTY also occurs in older adults, who frequently show BRAF V600E mutation. It also expands the spectrum of the MAPK pathway activating alterations associated with PLNTY and demonstrates recurrent chromosomal copy number changes consistent with chromosomal instability.

scholarly journals Establishment of Canine Transitional Cell Carcinoma Cell Lines Harboring BRAF V595E Mutation as a Therapeutic Target

2021 ◽  
Vol 22 (17) ◽  
pp. 9151
Author(s):  
Hyojik Jung ◽  
Kieun Bae ◽  
Ja Young Lee ◽  
Jung-Hyun Kim ◽  
Hyun-Jung Han ◽  
...  
Keyword(s):  
Transitional Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Human Cancer ◽  
Transitional Cell ◽  
Braf Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Tumor Tissues

Transitional cell carcinoma (TCC) is the most common malignant tumor of the canine urinary tract and tends to have a poor prognosis due to its invasive potential. Recent studies have reported that up to 80% of canine urothelial carcinoma has the BRAF V595E mutation, which is homologous to the human V600E mutation. Activating the BRAF mutation is an actionable target for developing effective therapeutic agents inhibiting the BRAF/mitogen-activated protein kinase (MAPK) pathway in canine cancer as well as human cancer. We established novel canine TCC cell lines from two tumor tissues and one metastatic lymph node of canine TCC patients harboring the BRAF V595E mutation. Tumor tissues highly expressed the BRAF mutant and phosphorylated extracellular signal-related kinases (ERK)1/2 proteins. The derived cell lines demonstrated activated MAPK pathways. We also evaluated the cell lines for sensitivity to BRAF inhibitors. Sorafenib, a multiple kinase inhibitor targeting RAF/vascular endothelial growth factor receptor (VEGFR), successfully inhibited the BRAF/MAPK pathway and induced apoptosis. The established canine TCC cell lines responded with greater sensitivity to sorafenib than to vemurafenib, which is known as a specific BRAF inhibitor in human cancer. Our results demonstrated that canine TCC cells showed different responses compared to human cancer with the BRAF V600E mutation. These cell lines would be valuable research materials to develop therapeutic strategies for canine TCC patients.

scholarly journals Identification of pathways modulating vemurafenib resistance in melanoma cells via a genome-wide CRISPR/Cas9 screen

2021 ◽  
Vol 11 (2) ◽  
Author(s):  
Corinna Jie Hui Goh ◽  
Jin Huei Wong ◽  
Chadi El Farran ◽  
Ban Xiong Tan ◽  
Cynthia R Coffill ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Enrichment Analysis ◽  
Melanoma Cells ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Genome Wide ◽  
A Genome ◽  
Mitogen Activated Protein ◽  
Genome Scale

Abstract Vemurafenib is a BRAF kinase inhibitor (BRAFi) that is used to treat melanoma patients harboring the constitutively active BRAF-V600E mutation. However, after a few months of treatment patients often develop resistance to vemurafenib leading to disease progression. Sequence analysis of drug-resistant tumor cells and functional genomic screens has identified several genes that regulate vemurafenib resistance. Reactivation of mitogen-activated protein kinase (MAPK) pathway is a recurrent feature of cells that develop resistance to vemurafenib. We performed a genome-scale CRISPR-based knockout screen to identify modulators of vemurafenib resistance in melanoma cells with a highly improved CRISPR sgRNA library called Brunello. We identified 33 genes that regulate resistance to vemurafenib out of which 14 genes have not been reported before. Gene ontology enrichment analysis showed that the hit genes regulate histone modification, transcription and cell cycle. We discuss how inactivation of hit genes might confer resistance to vemurafenib and provide a framework for follow-up investigations.

scholarly journals Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma

2017 ◽  
Author(s):  
Helma Zecena ◽  
Daniel Tveit ◽  
Zi Wang ◽  
Ahmed Farhat ◽  
Parvita Panchal ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Mapk Pathway ◽  
Treatment Resistance ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cellular Model ◽  
Braf Mutations ◽  
Mitogen Activated Protein ◽  
Inhibitor Resistance ◽  
Mapk Inhibitor

AbstractKinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. The cellular model evolved in response to clinical dosage of BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT-qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring based on non-genomic adaptation was validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. Downregulation of tumor suppressors and negative MAPK regulators, dual specific phosphatases, reengages mitogenic signaling. Upregulation of growth factors or cytokine receptors triggers signaling pathways circumventing BRAF blockage. Changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, an upregulation of pigmentation in inhibitor resistant melanoma cells was observed. Cellular pathways utilized during inhibitor resistance promoted melanogenesis, a pathway which partially overlaps with MAPK signaling. Upstream regulator analysis suggested gene expression changes of forkhead box and hypoxia inducible factor family transcription factors. The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine-woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy resistant cancer.

scholarly journals BRAF inhibitors promote intermediate BRAF(V600E) conformations and binary interactions with activated RAS

2019 ◽  
Vol 5 (8) ◽  
pp. eaav8463 ◽  
Author(s):  
Ruth Röck ◽  
Johanna E. Mayrhofer ◽  
Omar Torres-Quesada ◽  
Florian Enzler ◽  
Andrea Raffeiner ◽  
...  
Keyword(s):  
Resistance Mechanisms ◽  
Tumor Formation ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Drug Induced ◽  
Kinase Activation ◽  
Binding Domains ◽  
Intramolecular Communication ◽  
Sequential Formation

Oncogenic BRAF mutations initiate tumor formation by unleashing the autoinhibited kinase conformation and promoting RAS-decoupled proliferative RAF-MEK-ERK signaling. We have engineered luciferase-based biosensors to systematically track full-length BRAF conformations and interactions affected by tumorigenic kinase mutations and GTP loading of RAS. Binding of structurally diverse αC-helix-OUT BRAF inhibitors (BRAFi) showed differences in specificity and efficacy by shifting patient mutation–containing BRAF reporters from the definitive opened to more closed conformations. Unexpectedly, BRAFi engagement with the catalytic pocket of V600E-mutated BRAF stabilized an intermediate and inactive kinase conformation that enhanced binary RAS:RAF interactions, also independently of RAF dimerization in melanoma cells. We present evidence that the interference with RAS interactions and nanoclustering antagonizes the sequential formation of drug-induced RAS:RAF tetramers. This suggests a previously unappreciated allosteric effect of anticancer drug-driven intramolecular communication between the kinase and RAS-binding domains of mutated BRAF, which may further promote paradoxical kinase activation and drug resistance mechanisms.

TOXICITIES OF TARGETED THERAPY AND IMMUNE-RELATED ADVERSE DRUG REACTIONS OF IMMUNOTHERAPY IN THE TREATMENT OF METASTATIC MELANOMA

2018 ◽  
Author(s):  
Lidija Kandolf Sekulović
Keyword(s):  
Overall Survival ◽  
Targeted Therapy ◽  
Side Effects ◽  
Adverse Effects ◽  
Metastatic Melanoma ◽  
Adverse Drug Reactions ◽  
Mek Inhibitor ◽  
Braf Inhibitors ◽  
Drug Reactions ◽  
Acneiform Eruption

Targeted therapy and immunotherapy changed the treatment landscape for metastatic melanoma, which is chemotherapy resistant cancer. In pre-innovation era, the overall survival of patients with metastatic melanoma was 6 months, while today 5-year overall survival rate of 34% (and 50% in good prognostic groups) is evident. However, both treatments have their side effects, and cutaneous are the most frequent. Treating physicians in oncology centres, but also primary care specialists, need to be aware of their spectrum which differs for each class of drug: BRAF inhibitors, MEK inhibitors and immunotherapy with anti-PD1 and anti-CTLA4. While BRAF inhibitors have the most prominent adverse effects which are class specific, there are also drug-specific adverse effects. For example, vemurafenib causes photosensitivity, which is not specific for dabrafenib, while dabrafenib induces pyrexia, that occurs much less frequently with other BRAF inhibitors. Cutaneous rash and cutaneous neoplasms which develop due to paradoxical activation of RAS signalling are described with BRAF inhibitor monotherapy. These side-effects are much less common in combination therapy with BRAF and MEK inhibitor, but MEK inhibitor itself causes characteristic acneiform eruption, and serous retinopathy. Immune related adverse drug reactions are a hallmark of the immune checkpoint inhibitor immunotherapy, which can affect every organ system, and most commonly skin, lungs and gastrointestinal system, with differential frequencies recorded with anti-CTLA4 therapy and anti PD-1 therapy. Skin reactions most frequently include pruritus and eczematous reactions, as well as vitiligo-like hypopigmentation, which is linked Melanom 45 to the better response to treatment. In this review, frequent and rare side effects are presented, as well as the current algorithms for their treatment.

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