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Profile of Selumetinib and Its Potential in the Treatment of Melanoma

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Profile of Selumetinib and Its Potential in the Treatment of Melanoma OncoTargets and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article REVIEW Profile of selumetinib and its potential in the treatment of melanoma Dae Won Kim Abstract: The mitogen-activated protein kinase (MAPK) pathway is a critical oncogenic driver Sapna P Patel signal in a number of malignancies. The discovery of activating mutations in the MAPK pathway has led to the development of MAPK pathway inhibitors. Selumetinib is a potent and selective Department of Melanoma Medical Oncology, University of Texas MD inhibitor of MEK1 and MEK2, which are essential downstream molecules in the MAPK pathway. Anderson Cancer Center, Houston, Several preclinical and clinical studies have demonstrated the promising antitumor activity of TX, USA selumetinib. In this review, we discuss the MAPK pathway in melanoma and summarized data from preclinical and clinical studies of selumetinib for advanced melanoma. Keywords: selumetinib, MEK inhibitor, melanoma, uveal melanoma For personal use only. Introduction Melanoma is the most aggressive skin cancer, and both the incidence of melanoma and melanoma-related deaths have increased over the last several decades in the United States, with more than 76,000 new cases and more than 9,000 deaths predicted in 2013.1 A majority of patients with melanoma are diagnosed early with local disease, and surgical resection is the mainstay of treatment for localized melanoma with excellent outcome. In contrast, patients with metastatic melanoma have poor outcomes, with a 6–8 month median survival.2 Furthermore, the treatment for advanced melanoma is quite challenging. Until 2011, only two drugs, dacarbazine and recombinant human high-dose interleukin 2, were approved for the treatment of metastatic melanoma by OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.191.40.80 on 25-May-2017 the US Food and Drug Administration (FDA). Unfortunately, both drugs have a low response rate (5%–15%), and high-dose interleukin 2 also is associated with significant systemic toxicities.3 The rapid technical advancement in molecular biology and tumor immunology led to new treatment approaches such as targeted therapy and immunotherapy. Ipilimumab, a monoclonal anticytotoxic T-lymphocyte-associated antigen 4 antibody, was approved by the FDA in 2011 on the basis of significant improvement in progression-free survival (PFS) and overall survival (OS) compared with gp100 vaccine treatment.4 Recently, mitogen-activated protein kinase (MAPK) pathway inhibitors, including selective BRAF inhibitors (dabrafenib and vemurafenib) and a selective MEK inhibitor (trametinib), have shown significant improvement of PFS and OS over chemotherapy Correspondence: Sapna Patel in patients with BRAF mutant melanoma, which led to the approval of these drugs.5–7 MD Anderson Cancer Center, Melanoma Medical Oncology, 1515 Holcombe Blvd, Despite these promising new agents, the majority of metastatic melanomas are not Unit 0430, Houston, TX 77030, USA curable. Therefore, effective and novel approaches are still desperately needed for Tel +1 713 792 2921 Email [email protected] metastatic melanoma. submit your manuscript | www.dovepress.com OncoTargets and Therapy 2014:7 1631–1639 1631 Dovepress © 2014 Kim and Patel. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further http://dx.doi.org/10.2147/OTT.S51596 permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Powered by TCPDF (www.tcpdf.org) 1 / 1 Kim and Patel Dovepress MAPK pathway selumetinib have been extensively studied clinically as MEK One of the biggest milestones in melanoma research is the inhibitors in advanced solid tumors. identification ofBRAF gene mutations in melanoma.8 BRAF is one of the key molecules in the MAPK pathway, which is Selumetinib frequently dysregulated in human cancer.9 MAPK pathway, Preclinical studies composed of RAS-RAF-MEK-ERK, is associated with cell Selumetinib (AZD6244, ARRY-142886; AstraZeneca, proliferation and growth (Figure 1). Up to 75% of melanomas PLC, London, United Kingdom) is a highly selective, ATP- have dysregulated MAPK signaling pathway via BRAF (50%) uncompetitive allosteric inhibitor of both MEK1 and MEK2 or NRAS mutations (15%–25%), which results in unregulated and has the empirical formula of C17H15BrCLFN4O3 (Figure 2). 8,10 cell proliferation and growth. The half-maximal inhibitory concentration of selumetinib is 14.1 nmol/L against purified MEK1 in vitro, whereas no MEK inhibition inhibition of 40 other serine/threonine and tyrosine kinases Dysregulation of MAPK pathway in the majority of melanoma was observed at concentrations up to 10 µmol/L.13 and other malignancies, including colon, pancreatic, and non- small-cell lung cancer, makes MEK an attractive therapeutic NRAS/KRAS/BRAF mutant cancer cell lines target as one of the main downstream molecules of MAPK Although a majority of melanomas have dysregulated MAPK pathway. Initial preclinical studies of selective MEK inhibi- pathway via BRAF and NRAS mutations, 90% of pancreatic tors have been shown to have promising antitumor activities in cancers, 50% of colorectal cancers, and 25% of non-small- BRAF and NRAS mutant tumor cell lines.11,12 Solit et al showed cell lung cancers also have constitutively activated MAPK complete abrogation of BRAF mutant melanoma growth and pathway via KRAS mutations.14–16 Therefore, MAPK pathway partial inhibition of NRAS mutant melanoma growth in murine inhibition by selumetinib was evaluated in other malignan- xenografts with selective MEK inhibitors such as CI-1040 cies, including colorectal, pancreatic, non-small-cell lung, 12 For personal use only. and PD0325901. However, clinical development of these and hepatocellular cancer, as well as melanoma. MEK inhibitors, including CI-1040 and PD0325901, was Phosphorylation of ERK1/2, downstream molecules of discontinued because of a lack of clinical activity of CI-1040 MEK, was effectively inhibited with selumetinib in mela- and severe and frequent neurologic, musculoskeletal, and noma, colorectal cancer, pancreatic cancer, non-small-cell ocular toxicities of PD0325901. At this time, trametinib and lung cancer, and hepatocellular cancer cell lines harboring Receptor tyrosine kinase Extracellular OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 54.191.40.80 on 25-May-2017 Intracellular NRAS BRAF PI3K Selumetinib PTEN MEK1/2 AKT ERK Nucleus Cell proliferation and survival Figure 1 Melanoma signaling pathway. 1632 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2014:7 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Selumetinib in melanoma H lines by the mechanism of apoptosis, cell-cycle arrest, and HO N O reduced cellular migration and VEGF-A secretion in vitro O CI 26 H and in vivo. N Uveal melanoma Although uveal melanomas rarely have BRAF and NRAS mutations, the MAPK pathway is constitutively activated N F Br by GNAQ or GNA11 mutations that occur in approximately N 80% of primary uveal melanomas.27,28 Because direct phar- Figure 2 Chemical structure of selumetinib. macologic targeting of GNAQ/GNA11 mutations is not fea- sible, inhibition of the key downstream effectors of MAPK BRAF, NRAS, or KRAS mutations.13,17–19 However, growth pathway has been studied. In vitro studies have demonstrated suppression and the apoptotic effect of selumetinib varied that selumetinib monotherapy is not effective in inducing among the cancer cell lines.17,18 antitumor activity in uveal melanoma cell lines because of reciprocal activation of the c-JUN or PI3K/AKT pathway, Selumetinib-based combination treatment which is associated with cell proliferation, tumor cell inva- To overcome the inconsistent efficacy of selumetinib sion, and drug resistance.29,30 The combination of either c-Jun and enhance its antitumor activity, several combinatorial inhibition or PI3K/AKT inhibitors with selumetinib resulted approaches have been studied. The combined treatment with in the significant induction of apoptosis in uveal melanoma selumetinib and cytotoxic chemotherapy such as irinotecan, cell lines.29,30 Another preclinical study demonstrated that docetaxel, temozolomide, and doxorubicin resulted in signifi- the combination of selumetinib and a mammalian target of cant enhanced antitumor efficacy by both cell cycle arrest and rapamycin (mTOR) inhibitor (AZD8055) which is down- apoptosis in mice xenografts of BRAF mutant melanoma, as stream of PI3K/AKT pathway, induces tumor regression For personal use only. well as KRAS mutant colon cancer, non-small-cell lung can- in BRAF mutant uveal melanoma cell lines but not GNAQ cer, pancreatic cancer, and hepatocellular carcinoma.17,18,20,21 mutant cell lines.31 Unfortunately, these cell lines are likely Gopal et al have reported that the PI3K/AKT pathway plays a contaminants of cutaneous melanoma cell lines because critical role in the antitumor efficacy of selumetinib inBRAF BRAF mutations are not present in uveal melanoma. The mutant melanoma, and inhibition of PI3K/AKT pathway resistance to selumetinib plus AZD8055 in
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