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.

Genomic profiles of BRAF inhibitor resistance mechanisms in metastatic colorectal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15527-e15527
Author(s):  
Ting Xu ◽  
Xicheng Wang ◽  
Qi Changsong ◽  
Zhenghang Wang ◽  
Jian Li ◽  
...  
Keyword(s):  
Disease Progression ◽  
Signaling Pathway ◽  
Clinical Decision Making ◽  
Braf Inhibitor ◽  
Resistance Mechanisms ◽  
Genetic Alterations ◽  
Braf V600e ◽  
Plasma Samples ◽  
Braf Inhibitors ◽  
Braf Mutations

e15527 Background: BRAF mutations are present in 5-10% of metastatic colorectal cancers (mCRCs). Patients with mCRC whose tumors harbor BRAF V600 mutation generally respond poorly to standard chemotherapy. Treatment with BRAF inhibitors has been shown to improve outcomes, whereas the resistance develops through undefined mechanisms. Therefore, it is imperative to accurately comprehend the genomic profiling of resistance mechanisms to BRAF inhibitors in mCRC for exploring its clinical treatment strategies. Methods: We analyzed next-generation sequencing results in 520 cancer-associated genes for 22 patients who had BRAF V600E mutant mCRC in order to characterize genomic predictors of treatment outcome and track the acquired resistance (AR) mechanisms during the vemurafenib/dabrafenib/encorafenib treatment in combination with cetuximab +/- trametinib. The median age of the patients was 61 years old, 54.5% were male, 54.5% had right-sided mCRC, and 81.8% received one or more prior chemotherapy lines. Tissue and/or plasma samples were collected at baseline (prior to anti-BRAF treatment) and upon disease progression (PD). Objective tumor responses were radiologically assessed every 6 weeks according to RECIST v1. 1. Results: By Feb 2021, treatment had been discontinued in 15 (63.2%) of the patients due to disease progression, while the other 7 cases were still under treatment. The median PFS (mPFS) for all patients was 4.5 months. The overall response rate was 32%, and the disease control rate was 86%. In addition to BRAF V600E, the most common concomitant mutations were identified in TP53 (20/22), RNF43 (8/22), LRP18 (7/22), APC (7/22) and PIK3CA (5/22). Patients with baseline alterations in RNF43 (n = 8; p = 0.0466), or RECQL4 (n = 4; p = 0.0406) had significantly longer PFS than their respective wild type counterparts. In contrast, baseline alterations in PPP2R2A (n = 3; p = 0.0131), RUNX1T1 (n = 3; p = 0.0147), and receptor tyrosine kinase (RTK) signaling pathway genes (n = 6; p = 0.0057) were each significantly associated with shorter PFS. Among the 15 patients whose disease progressed, 9 were identified with newly developed AR mutations in PD tumor or plasma samples. MET amplification was the most common AR mechanism (n = 4) followed by BRAF amplification, KRAS, NRAS mutations (n = 3 each), and MAP2K1, PIK3R1 mutations (n = 1 each). Q61 substitution was the most dominant form for both KRAS and NRAS AR mutations (83%, 5/6). In terms of signaling pathway, MAPK (67%, 6/9) and RTK (44%, 4/9) pathway alterations were most frequently observed. Conclusions: Our study illustrated the landscape of genetic alterations in patients with BRAF V600E mutant mCRC upon BRAF inhibitor treatment, which could be critical to predict responses to BRAF inhibitors and guide personalized clinical decision-making after disease progression.

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.

Promising Strategies for Overcoming BRAF Inhibitor Resistance Based on Known Resistance Mechanisms

2020 ◽  
Vol 20 (12) ◽  
pp. 1415-1430 ◽  
Author(s):  
Qing-Shan Li ◽  
Bang-Nian Shen ◽  
Hua-Jian Xu ◽  
Ban-Feng Ruan
Keyword(s):  
Treatment Strategies ◽  
Braf Inhibitor ◽  
Resistance Mechanisms ◽  
Therapeutic Effects ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Clinical Benefits ◽  
Melanoma Patients ◽  
Inhibitor Resistance ◽  
Braf Mutant

Background: Almost 50% of metastatic melanomas harbor BRAF mutations. Since 2011, BRAF inhibitors have exhibited striking clinical benefits in BRAF-mutant melanoma patients. Unfortunately, their therapeutic effects are often temporary. The resistance mechanisms vary and can be broadly classified as MAPK reactivation-dependent and -independent. Elucidation of these resistance mechanisms provides new insights into strategies for overcoming resistance. Indeed, several alternative treatment strategies, including changes in the mode of administration, combinations of BRAF and MEK inhibitors, and immunotherapy have been verified as beneficial to BRAF inhibitor-resistant melanoma patients. Prospect: In this review, we discuss promising strategies for overcoming drug resistance and highlighting the prospects for discovering strategies to counteract BRAF inhibitor resistance.

scholarly journals Molecular targeted therapy of BRAF-mutant colorectal cancer

2019 ◽  
Vol 11 ◽  
pp. 175883591985649 ◽  
Author(s):  
Michel Ducreux ◽  
Ali Chamseddine ◽  
Pierre Laurent-Puig ◽  
Cristina Smolenschi ◽  
Antoine Hollebecque ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Poor Prognosis ◽  
Growth Factor Receptor ◽  
Braf Inhibitor ◽  
Braf V600e ◽  
Line Treatment ◽  
Second Line ◽  
Braf Inhibitors ◽  
First Line ◽  
Braf Mutations

Over the past two decades, the molecular characterization of metastatic colorectal cancer (mCRC) has been revolutionized by the routine implementation of RAS and BRAF tests. As a result, it is now known that patients with mCRC harboring BRAF mutations experience a poor prognosis. Although it accounts for only 10% of mCRC, this group is heterogeneous; only the BRAF-V600E mutation, also observed in melanoma, is associated with a very poor prognosis. In terms of treatment, these patients do not benefit from therapeutics targeting the epidermal growth factor receptor (EGFR). In first-line chemotherapy, there are two main options; the first one is to use a triple chemotherapy combination of 5-fluorouracil, irinotecan, and oxaliplatin, with the addition of bevacizumab, because post hoc analysis of randomized trials have reported interesting results. The other option is to use double chemotherapy plus bevacizumab, since anti-EGFR seems to have modest activity in these patients. Only a small percentage of patients who experience failure of this first-line treatment receive second-line treatment. Monotherapy with BRAF inhibitors has failed in this setting, and different combinations have also been tested. Using the rationale that BRAF inhibitor monotherapy fails due to feedback activation of the EGFR pathway, BRAF inhibitors have been combined with anti-EGFR agents plus or minus MEK inhibitors; however, the results did not live up to the hopes raised by the concept. To date, the best results in second-line treatment have been obtained with a combination of vemurafenib, cetuximab, and irinotecan. Despite these advances, further improvements are needed.

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.

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.

scholarly journals High prevalence of somatic MAP2K1 mutations in BRAF V600E–negative Langerhans cell histiocytosis

Blood ◽  
2014 ◽  
Vol 124 (10) ◽  
pp. 1655-1658 ◽  
Author(s):  
Noah A. Brown ◽  
Larissa V. Furtado ◽  
Bryan L. Betz ◽  
Mark J. Kiel ◽  
Helmut C. Weigelin ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Genome Sequencing ◽  
High Frequency ◽  
Langerhans Cell Histiocytosis ◽  
Langerhans Cell ◽  
Braf V600e ◽  
Braf Mutations ◽  
Key Points ◽  
High Prevalence

Key Points Targeted genome sequencing reveals high-frequency somatic MAP2K1 mutations in Langerhans cell histiocytosis. MAP2K1 mutations are mutually exclusive with BRAF mutations and may have implications for the use of BRAF and MEK targeted therapy.

SCRUM-Japan genesis virtual sequencing (VSQ) project: A novel algorithm combining deep learning (DL) with pathological diagnostics to enable the prediction of BRAF mutations and microsatellite instability (MSI) in advanced colorectal cancer (CRC).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 112-112
Author(s):  
Satoshi Fujii ◽  
Daisuke Kotani ◽  
Masahiro Hattori ◽  
Nishihara Masato ◽  
Toshihide Shikanai ◽  
...  
Keyword(s):  
Prediction Models ◽  
High Accuracy ◽  
Cancer Genome ◽  
Morphological Features ◽  
Braf V600e ◽  
Next Generation ◽  
Braf Mutations ◽  
Genetic Abnormalities ◽  
Image Prediction ◽  
Novel Algorithm

112 Background: Numerous genetic and epigenetic abnormalities may lead to various morphologies of cancer. However, exactly which gene abnormality causes which morphology is unknown. The VSQ Project aims at investigating a novel algorithm by synergistically fusing DL technology and pathological diagnostics for the prediction of cancer genome abnormalities. This was achieved by elucidating the association between the morphological findings and genetic abnormalities, including BRAF V600E mutations and MSI status directly linked to the therapeutic strategies for advanced CRC patients (pts). Methods: Clinicopathological-genomic integrated DB derived from SCRUM-Japan GI-SCREEN, a nation-wide cancer genome screening project including CRC, were used. A total of 1,657 images of thin sections (one representative image per pt) cut from formalin-fixed and paraffin-embedded (FFPE) tissue specimens from primary or metastatic tumors with genetic abnormalities confirmed by next-generation sequencing (NGS) were investigated; 1,234 and 423 images (one per pt) were used for training and validation cohorts, respectively. First, we developed image-prediction models based on the morphological features precisely annotated by the single central pathologist, and then constructed the DL algorithms (gene-prediction models) that enabled the prediction of gene abnormalities by using images filtered by the image-prediction models. Results: We achieved high accuracy of AUC > 0.90 for 12 features among the 33 morphological features analyzed. Next, we created several DL algorithms that enabled the prediction of BRAF mutations and MSI. The prediction level reached a high accuracy of AUC = 0.955 for the BRAF mutations and AUC = 0.857 for MSI in the training cohort. We verified the AUCs in the validation cohort and achieved AUC = 0.831 and 0.883 for BRAF mutations and MSI, respectively. Conclusions: Our findings suggest that VSQ can appropriately predict BRAF mutation and MSI status in advanced CRC, potentially without performing NGS tests. VSQ may also enable prompt initiation of systemic treatments in CRC patients as well as establish an unprecedented next-generation pathology in the near future.

scholarly journals BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Ryan J. Sullivan ◽  
Keith T. Flaherty
Keyword(s):  
Standard Of Care ◽  
Diagnostic Techniques ◽  
Therapeutic Interventions ◽  
Molecular Testing ◽  
Braf Inhibitors ◽  
Testing Methods ◽  
Braf Mutations ◽  
Initial Discovery ◽  
Braf Mutant ◽  
Mutant Braf

Since the initial discovery that a subset of patients with cutaneous melanoma harbor BRAF mutations, substantial research has been focused on determining the pathologic consequences of BRAF mutations, optimizing diagnostic techniques to identify these mutations, and developing therapeutic interventions to inhibit the function of this target in mutation-bearing tumors. Recently, advances have been made which are revolutionizing the standard of care for patients with BRAF mutant melanoma. This paper provides an overview on the pathogenic ramifications of mutant BRAF signaling, the latest molecular testing methods to detect BRAF mutations, and the most recent clinical data of BRAF pathway inhibitors in patients with melanoma and BRAF mutations. Finally, emerging mechanisms of resistance to BRAF inhibitors and ways of overcoming this resistance are discussed.

Sign in / Sign up

Export Citation Format

Share Document