title: MEK inhibition in the treatment of advanced melanoma.
abstract: The RAS-RAF-MEK-ERK pathway is considered to be the most important signal transduction pathway in melanoma, and alterations in this pathway via various genetic mutations, such as BRAF and NRAS mutations, are known to be important drivers of melanomagenesis. As MEK is an essential intermediary kinase protein within this pathway, inhibition of MEK has been of a great interest as a molecular target therapy in melanoma. In fact, trametinib, a selective MEK inhibitor, has been shown to have a survival benefit over cytotoxic chemotherapy in patients with V600 BRAF-mutant metastatic melanoma, leading to the FDA approval for this patient population. MEK inhibitors may also be useful in treatment of advanced melanoma harboring other genetic mutations, such as NRAS and GNAQ/GNA11 mutations. Here, we review and discuss the preclinical and clinical data regarding MEK inhibitors and their role in the treatment of advanced melanoma.
authors: Division of Medical Oncology, Duke University Medical Center, DUMC 3476, Durham, NC, 27710, USA, april.salama@duke.edu.
authors: April K S
authors: AK
authors: Salama
authors: Kevin B
authors: KB
authors: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy*; D058990:Molecular Targeted Therapy / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D020930:MAP Kinase Kinase Kinases
references: Cancer Chemother Pharmacol. 2011 Aug;68(2):547-52
references: 21516509
references: Clin Cancer Res. 2012 Jun 1;18(11):3090-9
references: 22496205
references: PLoS One. 2010 Dec 29;5(12):e15588
references: 21206909
references: Nature. 2010 Dec 16;468(7326):973-7
references: 21107323
references: Cancer Cell. 2004 Oct;6(4):313-9
references: 15488754
references: Nature. 2009 Jan 29;457(7229):599-602
references: 19078957
references: Clin Cancer Res. 2010 Mar 1;16(5):1613-23
references: 20179232
references: PLoS One. 2010 Nov 29;5(11):e14124
references: 21124782
references: Oncogene. 2011 Jan 20;30(3):366-71
references: 20818433
references: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6
references: 19915144
references: Nat Med. 2012 Oct;18(10):1503-10
references: 22983396
references: N Engl J Med. 2005 Nov 17;353(20):2135-47
references: 16291983
references: Lancet. 2012 Jul 28;380(9839):358-65
references: 22735384
references: Cancer Res. 2008 Jun 15;68(12):4853-61
references: 18559533
references: Mol Cancer Ther. 2008 Oct;7(10):3129-40
references: 18852116
references: Melanoma Res. 2006 Apr;16(2):97-103
references: 16567964
references: N Engl J Med. 2010 Dec 2;363(23):2191-9
references: 21083380
references: N Engl J Med. 2012 Jul 12;367(2):107-14
references: 22663011
references: N Engl J Med. 2010 Aug 19;363(8):711-23
references: 20525992
references: Clin Cancer Res. 2009 Dec 15;15(24):7711-7718
references: 19996224
references: Clin Cancer Res. 2012 Jan 15;18(2):555-67
references: 22048237
references: Biochim Biophys Acta. 2007 Aug;1773(8):1263-84
references: 17126425
references: Lancet Oncol. 2012 Aug;13(8):773-81
references: 22805291
references: J Clin Oncol. 2008 May 1;26(13):2139-46
references: 18390968
references: J Clin Oncol. 2006 Sep 10;24(26):4340-6
references: 16908931
references: Semin Oncol. 2003 Oct;30(5 Suppl 16):105-16
references: 14613031
references: N Engl J Med. 2011 Jun 30;364(26):2507-16
references: 21639808
references: J Clin Oncol. 2009 Jun 10;27(17):2823-30
references: 19349552
references: Clin Cancer Res. 2007 Mar 1;13(5):1576-83
references: 17332304
references: Nature. 2002 Jun 27;417(6892):949-54
references: 12068308
references: Oncogene. 2007 May 14;26(22):3279-90
references: 17496922
references: Nat Med. 1999 Jul;5(7):810-6
references: 10395327
references: Nature. 2010 Dec 16;468(7326):968-72
references: 21107320
references: Cancer Chemother Pharmacol. 2007 Apr;59(5):671-9
references: 16944149
references: Cell. 2010 Jan 22;140(2):209-21
references: 20141835
references: Cancer Res. 2005 Mar 15;65(6):2412-21
references: 15781657
references: Nature. 2010 Sep 30;467(7315):596-9
references: 20823850
references: J Clin Oncol. 2005 Aug 10;23(23):5281-93
references: 16009947
references: Lancet Oncol. 2012 Aug;13(8):782-9
references: 22805292
references: Clin Cancer Res. 2012 Jun 15;18(12):3242-9
references: 22535154
references: Lancet Oncol. 2013 Mar;14(3):249-56
references: 23414587
references: J Clin Oncol. 2013 May 10;31(14):1767-74
references: 23569304
references: J Clin Oncol. 2009 Dec 20;27(36):6199-206
references: 19917835
references: J Clin Oncol. 2004 Nov 15;22(22):4456-62
references: 15483017
references: Mol Cancer. 2012 Oct 05;11:75
references: 23039341
references: Ophthalmology. 2003 May;110(5):956-61
references: 12750097
references: Clin Cancer Res. 2013 Apr 15;19(8):2257-64
references: 23444215
references: Br J Dermatol. 2011 Apr;164(4):776-84
references: 21166657
references: N Engl J Med. 2012 Nov;367(18):1694-703
references: 23020132
references: Clin Cancer Res. 2010 Apr 15;16(8):2450-7
references: 20332327
references: Cancer Res. 2004 Oct 1;64(19):7099-109
references: 15466206
references: Clin Cancer Res. 2011 Mar 1;17(5):989-1000
references: 21245089
references: Clin Cancer Res. 2010 Mar 15;16(6):1924-37
references: 20215549
references: Cancer. 2013 Feb 15;119(4):799-805
references: 22972589