Inhibition of Mutated, Activated BRAF in Metastatic Melanoma

Abramson Cancer Center of the University of Pennsylvania, Philadelphia, USA.
New England Journal of Medicine (Impact Factor: 55.87). 08/2010; 363(9):809-19. DOI: 10.1056/NEJMoa1002011
Source: PubMed

ABSTRACT The identification of somatic mutations in the gene encoding the serine-threonine protein kinase B-RAF (BRAF) in the majority of melanomas offers an opportunity to test oncogene-targeted therapy for this disease.
We conducted a multicenter, phase 1, dose-escalation trial of PLX4032 (also known as RG7204), an orally available inhibitor of mutated BRAF, followed by an extension phase involving the maximum dose that could be administered without adverse effects (the recommended phase 2 dose). Patients received PLX4032 twice daily until they had disease progression. Pharmacokinetic analysis and tumor-response assessments were conducted in all patients. In selected patients, tumor biopsy was performed before and during treatment to validate BRAF inhibition.
A total of 55 patients (49 of whom had melanoma) were enrolled in the dose-escalation phase, and 32 additional patients with metastatic melanoma who had BRAF with the V600E mutation were enrolled in the extension phase. The recommended phase 2 dose was 960 mg twice daily, with increases in the dose limited by grade 2 or 3 rash, fatigue, and arthralgia. In the dose-escalation cohort, among the 16 patients with melanoma whose tumors carried the V600E BRAF mutation and who were receiving 240 mg or more of PLX4032 twice daily, 10 had a partial response and 1 had a complete response. Among the 32 patients in the extension cohort, 24 had a partial response and 2 had a complete response. The estimated median progression-free survival among all patients was more than 7 months.
Treatment of metastatic melanoma with PLX4032 in patients with tumors that carry the V600E BRAF mutation resulted in complete or partial tumor regression in the majority of patients. (Funded by Plexxikon and Roche Pharmaceuticals.)

Download full-text


Available from: Joseph F Grippo, Sep 26, 2015
60 Reads
    • "Recurrent mutations that disrupt the same gene can be highly informative, pinpointing oncogenic alterations that may serve as therapeutic targets (Baselga et al., 1996; Druker et al., 2001; Flaherty et al., 2010). But focal alterations are relatively infrequent in many cancers, particularly those arising in children (Alexandrov et al., 2013; Zhang et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Choroid plexus carcinomas (CPCs) are poorly understood and frequently lethal brain tumors with few treatment options. Using a mouse model of the disease and a large cohort of human CPCs, we performed a cross-species, genome-wide search for oncogenes within syntenic regions of chromosome gain. TAF12, NFYC, and RAD54L co-located on human chromosome 1p32-35.3 and mouse chromosome 4qD1-D3 were identified as oncogenes that are gained in tumors in both species and required for disease initiation and progression. TAF12 and NFYC are transcription factors that regulate the epigenome, whereas RAD54L plays a central role in DNA repair. Our data identify a group of concurrently gained oncogenes that cooperate in the formation of CPC and reveal potential avenues for therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cancer cell 05/2015; 27(5):712-727. DOI:10.1016/j.ccell.2015.04.005 · 23.52 Impact Factor
  • Source
    • "dabrafenib. These anti-BRAF V600E therapies have led to improvements in the survival of patients with melanomas harboring the BRAF V600E mutation (Flaherty et al., 2010). However, most patients treated with BRAF inhibitors (BRAFi) develop resistance to these therapies after only several months (Flaherty et al., 2012; Franco et al., 2011; Sullivan and Flaherty, 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance to BRAF inhibitors (BRAFi) is one of the major challenges for targeted therapies for BRAF mutant melanomas. However, little is known about the role of microRNAs in conferring BRAFi-resistance. Herein, we demonstrate that miR-200c expression is significantly reduced whereas miR-200c target genes including Bmi1, Zeb2, Tubb3, ABCG5 and MDR1 are significantly increased in melanomas that acquired BRAFi resistance compared to pre-treatment tumor biopsies. Similar changes were observed in BRAFi-resistant melanoma cell lines. Overexpression of miR-200c or knockdown of Bmi1 in resistant melanoma cells restores their sensitivities to BRAFi, leading to deactivation of the PI3K/AKT and MAPK signaling cascades, and acquisition of epithelial-mesenchymal transition-like phenotypes, including up-regulation of E-cadherin, down-regulation of N-cadherin, and ABCG5 and MDR1 expression. Conversely, knockdown of miR-200c or overexpression of Bmi1 in BRAFi-sensitive melanoma cells activates the PI3K/AKT and MAPK pathways, upregulates N-cadherin, ABCG5 and MDR1 expression, and downregulation of E-cadherin expression, leading to BRAFi-resistance. Together, our data identify miR-200c as a critical signaling node in BRAFi-resistant melanomas impacting the MAPK and PI3K/AKT pathways, suggesting miR-200c as a potential therapeutic target for overcoming acquired BRAFi resistance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 04/2015; 28(4). DOI:10.1111/pcmr.12379 · 4.62 Impact Factor
  • Source
    • "Cancer pharmacogenomics is more complicated since it must take into account both the germline and somatic genomes of the tumor [7]. After sequencing a large amount of kinase genes that exhibit somatic variations in tumors, pharmacogenetic research identified a specific inhibitor, vemurafenib, which can effectively prolong the survival of patients who carry a somatic mutation in BRAF [8]. Other researchers have shown that variations in the germline genomes of patients are clinically relevant and may affect anti-cancer drug therapy [9] [10]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Pharmacogenomics is the study of the impact of genetic variations or genotypes of individuals on their drug response or drug metabolism. Compared to traditional genomics research, pharmacogenomic research is more closely related to clinical practice. Pharmacogenomic discoveries may effectively assist clinicians and healthcare providers in determining the right drugs and proper dose for each patient, which can help avoid side effects or adverse reactions, and improve the drug therapy. Currently, pharmacogenomic approaches have proven their utility when it comes to the use of cardiovascular drugs, antineoplastic drugs, aromatase inhibitors, and agents used for infectious diseases. The rapid innovation in sequencing technology and genome-wide association studies has led to the development of numerous data resources and dramatically changed the landscape of pharmacogenomic research. Here we describe some of these web resources along with their names, web links, main contents, and our ratings. Copyright © 2015. Production and hosting by Elsevier Ltd.
    Genomics Proteomics & Bioinformatics 02/2015; 364(1). DOI:10.1016/j.gpb.2015.01.002
Show more