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.

OS02.4.A Molecular characterization of adult cerebellar glioblastomas identifies distinct prognosis subgroups

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii5-ii5
Author(s):  
T Picart ◽  
D Poncet ◽  
M Barritault ◽  
J Pallud ◽  
P Metellus ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Targeted Sequencing ◽  
Braf Mutations ◽  
Molecular Alterations ◽  
Activating Mutations ◽  
Diagnosis And Prognosis ◽  
Induced Tumors ◽  
Radiation Induced

Abstract BACKGROUND Adult cerebellar glioblastomas (cGBM) are very rare and recent studies have shown that they constitute a heterogeneous group of gliomas. The aim of the present study was to characterize the prevalence and prognostic significance of major driver molecular alterations in a large series of cGBM. MATERIAL AND METHODS Adults with histologically proven cGBM diagnosed between 2003 and 2017 were identified from the French brain tumor database and the Club de Neuro-Oncologie of the Société Française de Neurochirurgie. Tumors were reviewed and reclassified according to WHO 2016. Targeted sequencing was performed, including determination of H3F3A, TERTp, IDH1/2, FGFR1, BRAF and EGFR status. RESULTS A total of 83 adult patients (median age 57 years) with cGBM (hemispheric n= 47, vermian n=14 or both n=22) were identified. Median overall survival was 10 months. Main molecular alterations observed were TERT promoter, H3F3A K27M, hotspot FGFR1 (N546 and K656), BRAF mutations, EGFR amplification and ATRX loss of expression in 19.2%, 18.8%, 10.9%, 2.6%, 19.5% and 22.7% of patients, respectively. cGBM could be classified into 6 mutually exclusive subgroups associated with age at diagnosis and prognosis: pTERT and/or EGFR amplified tumors (n=22, 26.5%, median age = 62 years, median OS = 4 months), H3K27M-mutant tumors (n=15, 18.1%, median age = 48 years, median OS =8 months), tumors with MAPK pathway activating mutations (FGFR1, BRAF) or occurring in NF1 patients (n=15, 18.1%, median age = 41 years, median OS = 57 months), radiation-induced tumors (n=5, 6%, median age = 47 years, median OS = 5 months), IDH-mutant tumors (n=1) and unclassified tumors (n=25, 30.1%, median age = 63 years, median OS = 17 months). In multivariate analysis, MAPK activating mutations and ATRX loss of expression were independently associated with a better outcome and pTERT/EGFR alterations with a worse outcome. CONCLUSION About 18% of tumors diagnosed as cGBM harbor actionable MAPK activating genetic alterations. Targeted sequencing enables to classify these tumors into clinically relevant subgroups.

scholarly journals DDRE-07. DIPG HARBOUR ALTERATIONS TARGETABLE BY MEK INHIBITORS, WITH ACQUIRED RESISTANCE MECHANISMS OVERCOME BY COMBINATORIAL INHIBITION

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii62-ii62
Author(s):  
Elisa Izquierdo ◽  
Diana Carvalho ◽  
Alan Mackay ◽  
Sara Temelso ◽  
Jessica K R Boult ◽  
...  
Keyword(s):  
Drug Exposure ◽  
Mapk Pathway ◽  
Synergistic Effects ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Mesenchymal Transition

Abstract The survival of children with diffuse intrinsic pontine glioma (DIPG) remains dismal, with new treatments desperately needed. In the era of precision medicine, targeted therapies represent an exciting treatment opportunity, yet resistance can rapidly emerge, playing an important role in treatment failure. In a prospective biopsy-stratified clinical trial, we combined detailed molecular profiling (methylation BeadArray, exome, RNAseq, phospho-proteomics) linked to drug screening in newly-established patient-derived models of DIPG in vitro and in vivo. We identified a high degree of in vitro sensitivity to the MEK inhibitor trametinib (GI50 16-50nM) in samples, which harboured genetic alterations targeting the MAPK pathway, including the non-canonical BRAF_G469V mutation, and those affecting PIK3R1 and NF1. However, treatment of PDX models and of a patient with trametinib at relapse failed to elicit a significant response. We generated trametinib-resistant clones (62-188-fold, GI50 2.4–5.2µM) in the BRAF_G469V model through continuous drug exposure, and identified acquired mutations in MEK1/2 (MEK1_K57N, MEK1_I141S and MEK2_I115N) with sustained pathway up-regulation. These cells showed the hallmarks of mesenchymal transition, and expression signatures overlapping with inherently trametinib-insensitive primary patient-derived cells that predicted an observed sensitivity to dasatinib. Combinations of trametinib with dasatinib and the downstream ERK inhibitor ulixertinib showed highly synergistic effects in vitro. These data highlight the MAPK pathway as a therapeutic target in DIPG, and show the importance of parallel resistance modelling and rational combinatorial treatments likely to be required for meaningful clinical translation.

scholarly journals A Rare p.T599dup BRAF Mutant NSCLC in a Non-Smoker

2020 ◽  
Vol 28 (1) ◽  
pp. 196-202
Author(s):  
Alla Turshudzhyan ◽  
James Vredenburgh
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Braf Mutations ◽  
Activating Mutations ◽  
Extracellular Signal ◽  
Activating Mutation ◽  
Mitogen Activated Protein ◽  
Murine Sarcoma

V-RAF murine sarcoma viral oncogene homolog B1 (BRAF) mutated non-small-cell lung cancer (NSCLC) is an exceptionally rare form of lung cancer, found only in one to two percent of patients with an NSCLC diagnosis. BRAF NSCLC traditionally affects former or active smokers. BRAF mutations have always been of special interest to the oncological community, as they offer potential for targeted therapies. BRAF mutation spectrum includes mutations that are of both V600 and non-V600 types. BRAF V600 is an activating mutation, which results in high kinase activity and overproduction of active oncoproteins such as rapidly accelerated fibrosarcoma (RAF). This makes them susceptible to targeted therapies with RAF inhibitors. There has been little evidence, however, regarding efficacy of RAF inhibitors towards non-activating mutations that have intermediate to low kinase activity, such as non-V600 BRAF mutations. While several approaches have been investigated to overcome the limitations of RAF inhibitors, such as use of mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) inhibitors or combination of MEK and RAF inhibitors, none of them have been proven to have a superior efficacy for low kinase activity non-V600 BRAF tumors. We present a case of an extremely rare variant of NSCLC BRAF p.T599dup mutation in a non-smoker that responded to a targeted combination therapy with RAF and MEK inhibitors. The patient responded well to therapy that usually targets high kinase activity V600 mutations. Our hope is to bring more attention to non-V600 mutations and document their responses to existing and new therapies.

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.

A Career in Lung Cancer: Pushing Beyond Chemotherapy

2019 ◽  
pp. 583-589
Author(s):  
Pradnya Dinkar Patil ◽  
Frances Shepherd ◽  
David H. Johnson
Keyword(s):  
Lung Cancer ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Genetic Alterations ◽  
Disease Biology ◽  
Formidable Challenge ◽  
Treatment Paradigm

The landscape of treatments for non–small cell lung cancer (NSCLC) has evolved dramatically over the past 3 decades. A better understanding of the disease biology and identification of actionable genetic alterations heralded an era of targeted therapies that has led to unprecedented survival benefits in patients with oncogene-driven NSCLC. More recent breakthroughs in immunotherapy led to the development of immune checkpoint inhibitors that have changed the treatment paradigm for patients with advanced NSCLC because of their ability to produce durable responses, resulting in improved survival outcomes. Despite the unparalleled success of these agents, primary and acquired resistance to these therapies pose a formidable challenge. In this article, we provide an overview of the therapeutic advances in the treatment of NSCLC, mechanisms of resistance, and potential strategies to overcome resistance to targeted therapies and immune checkpoint inhibitors.

scholarly journals Dissecting Mechanisms of Melanoma Resistance to BRAF and MEK Inhibitors Revealed Genetic and Non-Genetic Patient- and Drug-Specific Alterations and Remarkable Phenotypic Plasticity

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 142 ◽  
Author(s):  
Mariusz L. Hartman ◽  
Malgorzata Sztiller-Sikorska ◽  
Anna Gajos-Michniewicz ◽  
Malgorzata Czyz
Keyword(s):  
Phenotypic Plasticity ◽  
Cell Lines ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Resistant Cell ◽  
Cross Resistance ◽  
Preclinical Model ◽  
Development Of Resistance

The clinical benefit of MAPK pathway inhibition in BRAF-mutant melanoma patients is limited by the development of acquired resistance. Using drug-naïve cell lines derived from tumor specimens, we established a preclinical model of melanoma resistance to vemurafenib or trametinib to provide insight into resistance mechanisms. Dissecting the mechanisms accompanying the development of resistance, we have shown that (i) most of genetic and non-genetic alterations are triggered in a cell line- and/or drug-specific manner; (ii) several changes previously assigned to the development of resistance are induced as the immediate response to the extent measurable at the bulk levels; (iii) reprogramming observed in cross-resistance experiments and growth factor-dependence restricted by the drug presence indicate that phenotypic plasticity of melanoma cells largely contributes to the sustained resistance. Whole-exome sequencing revealed novel genetic alterations, including a frameshift variant of RBMX found exclusively in phospho-AKThigh resistant cell lines. There was no similar pattern of phenotypic alterations among eleven resistant cell lines, including expression/activity of crucial regulators, such as MITF, AXL, SOX, and NGFR, which suggests that patient-to-patient variability is richer and more nuanced than previously described. This diversity should be considered during the development of new strategies to circumvent the acquired resistance to targeted therapies.

Emerging Strategies in Systemic Therapy for the Treatment of Melanoma

2018 ◽  
pp. 751-758 ◽  
Author(s):  
Paolo A. Ascierto ◽  
Keith Flaherty ◽  
Stephanie Goff
Keyword(s):  
Targeted Therapy ◽  
Targeted Therapies ◽  
De Novo ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Acquired Resistance ◽  
Interleukin 2 ◽  
Advanced Melanoma ◽  
Adoptive Cell Transfer ◽  
Mek Inhibition

Recent years have seen major improvements in survival of patients with advanced melanoma with the advent of various novel systemic immunotherapies and targeted therapies. As our understanding of these agents and their various mechanisms of action improves, even more impressive outcomes are being achieved through use of various combination strategies, including the combining of different immunotherapies with one another as well as with other modalities. However, despite the improved outcomes that have been achieved in advanced melanoma, responses to treatment are heterogeneous and may not always be durable. Additional advances in therapy are required, and several emerging strategies are a focus of interest. These include the investigation of several new immunotherapy and/or targeted therapy combinations, such as checkpoint inhibitors (anti–PD-1/anti–CTLA-4) with other immunotherapies (e.g., indoleamine 2,3 dioxygenase [IDO] inhibitors, antilymphocyte activation 3 [anti–LAG-3], histone deacetylase [HDAC] inhibitors, Toll-like receptor 9 [TLR-9] agonists, antiglucocorticoid-induced tumor necrosis factor receptor [anti-GITR], pegylated interleukin-2 [IL-2]), combined targeted therapies (e.g., MEK and CDK4/6 coinhibition), and combined immunotherapy and targeted therapy (e.g., the triplet combination of BRAF/MEK inhibition with anti–PD-1s). The identification of novel therapeutic targets in the MAP kinase pathway also offers opportunities to improve outcomes by overcoming de novo and acquired resistance to BRAF/MEK inhibition (e.g., the development of ERK inhibitors). In addition, adoptive cell transfer, the infusion of large numbers of activated autologous lymphocytes, may have a potential role in patients whose disease has progressed after immunotherapy. Taken together, these new approaches offer further potential to increase systemic treatment options and improve long-term outcomes for patients with advanced melanoma.

MAPK pathway inhibition in melanoma: resistance three ways

2014 ◽  
Vol 42 (4) ◽  
pp. 727-732 ◽  
Author(s):  
Claudia Wellbrock
Keyword(s):  
Mapk Pathway ◽  
Acquired Resistance ◽  
Tumour Microenvironment ◽  
Resistance Mechanisms ◽  
Melanoma Cells ◽  
Advanced Melanoma ◽  
Mitogen Activated Protein Kinase ◽  
Compensatory Mechanisms ◽  
Stromal Fibroblasts ◽  
Paracrine Signalling

The serine threonine kinases BRAF and MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] are major regulators of the ERK/MAPK pathway, which is deregulated in the majority of melanomas. Targeting BRAF is an effective therapy for advanced melanoma, but patients progress due to the development of resistance. This ‘acquired resistance’ is thought to be based on a minority of tumour cell populations that are resistant and will eventually re-establish tumour growth even in the presence of drug. In particular, mutations, amplifications or overexpression of genes encoding regulators of the MAPK pathway can confer this resistance, because it allows the melanoma cells to bypass inhibitor action by stimulating ERK activation through alternative routes. Furthermore, there are mechanisms that produce resistance by enhancing the tolerance of melanoma cells to the cytotoxic effects of the drug. These compensatory mechanisms can activate survival signals in the melanoma cells without reactivating ERK. Besides these cell-autonomous resistance mechanisms, stromal fibroblasts in the tumour microenvironment have been identified as a potential source of resistance, because these cells can produce growth factors that reactivate ERK through paracrine signalling. Understanding and further identifying mechanisms of resistance is crucial for the future treatment of advanced melanoma, because this can inform the design of improved therapies with more durable responses.

The clinical impact of quantitative cell-free DNA, KRAS, and BRAF mutations on response to anti-EGFR treatment in patients with metastatic colorectal cancer

2020 ◽  
Vol 26 ◽  
Author(s):  
Reyhaneh Moradi-Marjaneh ◽  
Fereshteh Asgharzadeh ◽  
Elnaz Khordad ◽  
Mahdi Moradi Marjaneh
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Current Knowledge ◽  
Acquired Resistance ◽  
Clinical Importance ◽  
Egfr Inhibitors ◽  
Braf Mutations ◽  
Cell Free Dna ◽  
Free Dna ◽  
Mutational Status

: Colorectal cancer (CRC) is one of the most common leading causes of cancer death in the world. Although EGFR inhibitors have established efficacy in metastatic colorectal cancer (mCRC), some patients do not respond to this treatment. The EGFR inhibitors failure and acquired resistance is partly due to KRAS and BRAF mutations. Thus, prognostic biomarkers that help to select eligible patients are highly in demand. To improve patient selection, assessment of mutational status in circulating cell free DNA (cfDNA), which possibly represents the dynamicity of tumor genetic status better than tumor tissue, could be advantageous. This review summarizes the current knowledge on the prognostic value of cfDNA in patients with mCRC treated with EGFR inhibitors with emphasis on the clinical importance of identification of KRAS and BRAF mutations.

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