The potential for BRAF V600 inhibitors in advanced cutaneous melanoma: rationale and latest evidence

Sarah Cannon Research UK, London and University College London, London, UK.
rapeutic Advances in Medical Oncology, The (Impact Factor: 2.83). 03/2012; 4(2):61-73. DOI: 10.1177/1758834011432949
Source: PubMed


Historically, patients with advanced cutaneous melanoma have a poor prognosis and limited treatment options. The discovery of selective v-raf murine sarcoma viral oncogene homolog B1 (BRAF) V600 mutation as an oncogenic mutation in cutaneous melanoma and the importance of the mitogen-activated protein kinase (MAPK) pathway in its tumourigenesis have changed the treatment paradigm for melanoma. Selective BRAF inhibitors and now MEK inhibitors have demonstrated response rates far higher than standard chemotherapeutic options and we review the phase I-III results for these agents in this article. The understanding of mechanisms of resistance that may occur upstream, downstream, at the BRAF level or bypassing the MAPK pathway provides a platform for rational drug development and combination therapies.

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    • "Mutations at this position result in the oncogene being constitutively activated with increased kinase activity and have been found in a wide range of cancers such as metastatic melanoma [80], ovarian serous carcinoma [81] and hairy cell leukemia [82]. Furthermore, recent inhibitors, such as Vemurafenib and GSK2118436 specifically target the V600E and V600E/K mutations (respectively), supporting the hypothesis that somatic clusters can provide pharmacological targets [83]. Lastly, segment III is comprised of the much less common K601N mutation which has been observed in myeloma cases along with V600E. "
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    ABSTRACT: BackgroundIt is well known that the development of cancer is caused by the accumulation of somatic mutations within the genome. For oncogenes specifically, current research suggests that there is a small set of "driver" mutations that are primarily responsible for tumorigenesis. Further, due to recent pharmacological successes in treating these driver mutations and their resulting tumors, a variety of approaches have been developed to identify potential driver mutations using methods such as machine learning and mutational clustering. We propose a novel methodology that increases our power to identify mutational clusters by taking into account protein tertiary structure via a graph theoretical approach.ResultsWe have designed and implemented GraphPAC (Graph Protein Amino acid Clustering) to identify mutational clustering while considering protein spatial structure. Using GraphPAC, we are able to detect novel clusters in proteins that are known to exhibit mutation clustering as well as identify clusters in proteins without evidence of prior clustering based on current methods. Specifically, by utilizing the spatial information available in the Protein Data Bank (PDB) along with the mutational data in the Catalogue of Somatic Mutations in Cancer (COSMIC), GraphPAC identifies new mutational clusters in well known oncogenes such as EGFR and KRAS. Further, by utilizing graph theory to account for the tertiary structure, GraphPAC discovers clusters in DPP4, NRP1 and other proteins not identified by existing methods. The R package is available at: provides an alternative to iPAC and an extension to current methodology when identifying potential activating driver mutations by utilizing a graph theoretic approach when considering protein tertiary structure.
    BMC Bioinformatics 06/2013; 14(1):190. DOI:10.1186/1471-2105-14-190 · 2.58 Impact Factor
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    • "Although BRAF mutation in metastatic melanoma portends a poor prognosis, it predicts response to targeted BRAF inhibitors [8] [19] [20]. Primary melanomas from acral and mucosal sites less frequently harbor BRAF mutations, found in only 10-15% of such cases [8] [19] [23]. Consistent with these results, it is not surprising that the melanoma in our case, which arose from teratomatous respiratory mucosa, was negative for a BRAF mutation. "
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    ABSTRACT: Mixed germ cell tumors are rare neoplasms that are known to occur in the anterior mediastinum. Characterized by two or more types of germ cell components, these tumors comprise upwards of 25% of mediastinal germ cell tumors. Even rarer are those harboring somatic-type malignancies such as carcinoma, sarcoma, and hematopoietic malignancies. To date, however, there are no known cases of melanoma arising in a malignant mixed germ cell tumor of the anterior mediastinum. We describe the first case of malignant melanoma with spindle and epithelioid components arising from respiratory epithelium in a mediastinal malignant mixed germ cell tumor of a 32-year-old male. In addition, we also provide evidence supporting the theory of neuroendocrine cells as the origin of melanoma arising in the respiratory epithelium. This case emphasizes the need to carefully evaluate all germ cell tumors, not only for a myriad of benign embryological components, but also for malignancies arising in these components, as they might change the prognosis and patient's course of treatment. This microscopic approach should bring to light the diversity of mixed germ cell tumors in addition to somatic malignancies with corresponding biologic potentials.
    International journal of clinical and experimental pathology 11/2012; 5(9):982-90. · 1.89 Impact Factor
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    • "Inhibition of BRAF combined with MEK should have the potential to address both outstanding issues, since MEK is a common downstream component of RAF and RAS signaling [12,13]. Evidence of positive results from dual BRAF and MEK inhibition in clinical trials is starting to emerge (vemurafenib and GDC-0973 currently in phase II), and effective evaluation of these drugs is important [14,15]. "
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    ABSTRACT: The BRAF inhibitor, vemurafenib, has recently been approved for the treatment of metastatic melanoma in patients harboring BRAFV600 mutations. Currently, dual BRAF and MEK inhibition are ongoing in clinical trials with the goal of overcoming the acquired resistance that has unfortunately developed in some vemurafenib patients. FDG-PET measures of metabolic activity are increasingly employed as a pharmacodynamic biomarker for guiding single-agent or combination therapies by gauging initial drug response and monitoring disease progression. However, since tumors are inherently heterogeneous, investigating the effects of BRAF and MEK inhibition on FDG uptake in a panel of different melanomas could help interpret imaging outcomes. 18 F-FDG uptake was measured in vitro in cells with wild-type and mutant (V600) BRAF, and in melanoma cells with an acquired resistance to vemurafenib. We treated the cells with vemurafenib alone or in combination with MEK inhibitor GDC-0973. PET imaging was used in mice to measure FDG uptake in A375 melanoma xenografts and in A375 R1, a vemurafenib-resistant derivative. Histological and biochemical studies of glucose transporters, the MAPK and glycolytic pathways were also undertaken. We demonstrate that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous BRAFV600 but ineffective in cells with acquired resistance or having WT BRAF status. However, combination with GDC-0973 results in a highly significant increase of efficacy and inhibition of FDG uptake across all twenty lines. Drug-induced changes in FDG uptake were associated with altered levels of membrane GLUT-1, and cell lines harboring RAS mutations displayed enhanced FDG uptake upon exposure to vemurafenib. Interestingly, we found that vemurafenib treatment in mice bearing drug-resistant A375 xenografts also induced increased FDG tumor uptake, accompanied by increases in Hif-1α, Sp1 and Ksr protein levels. Vemurafenib and GDC-0973 combination efficacy was associated with decreased levels of hexokinase II, c-RAF, Ksr and p-MEK protein. We have demonstrated that 18 F-FDG-PET imaging reflects vemurafenib and GDC-0973 action across a wide range of metastatic melanomas. A delayed post-treatment increase in tumor FDG uptake should be considered carefully as it may well be an indication of acquired drug resistance. NCT01271803.
    EJNMMI Research 05/2012; 2(1):22. DOI:10.1186/2191-219X-2-22
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