title: Targeting the MAPK pathway in melanoma: why some approaches succeed and other fail.
abstract: The Mitogen Activated Protein Kinase (MAPK) pathway plays a key role in melanoma development making it an important therapeutic target. In normal cells, the tightly regulated pathway relays extracellular signals from cell membrane to nucleus via a cascade of phosphorylation events. In melanomas, dysregulation of the MAPK pathway occurs frequently due to activating mutations in the B-RAF and RAS genes or other genetic or epigenetic modifications, leading to increased signaling activity promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. However, identification of ideal pathway member to therapeutically target for maximal clinical benefit to melanoma patients remains a challenge. This review provides an overview of the obstacles faced targeting the MAPK pathway and why certain therapeutic approaches succeed while others fail. The review summarizes the roles played by the proteins, therapeutic potential and the drugs available to target each member of the pathway as well as concerns related to each. Potential for targeting multiple points and inhibiting other pathways along with MAPK inhibition for optimal efficacy are discussed along with explanations for development of drug resistance, which includes discussions related to cross-talk between pathways, RAF kinase isoform switching and phosphatase deregulation. Finally, the use of nanotechnology is reviewed as an approach to target the MAPK pathway using both genetic and pharmacological agents simultaneously targeting multiple points in the pathway or in combination with other cascades.
authors.affiliation: Departments of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors.forename: Gajanan S
authors.initials: GS
authors.lastname: Inamdar
authors.forename: SubbaRao V
authors.initials: SV
authors.lastname: Madhunapantula
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000187:drug effects; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
references.citation: J Natl Cancer Inst. 2010 Feb 24;102(4):214-5
references.pmid: 20145213
references.citation: Cancer Res. 2004 Aug 15;64(16):5556-9
references.pmid: 15313890
references.citation: Nature. 2006 Jan 19;439(7074):358-62
references.pmid: 16273091
references.citation: J Cell Biochem. 2006 Apr 15;97(6):1184-90
references.pmid: 16440317
references.citation: Nanomedicine. 2005 Mar;1(1):22-30
references.pmid: 17292054
references.citation: Cancer Res. 2004 Apr 1;64(7):2338-42
references.pmid: 15059882
references.citation: Curr Biol. 2005 Feb 8;15(3):249-54
references.pmid: 15694309
references.citation: Cancer Res. 2008 Jun 15;68(12):4853-61
references.pmid: 18559533
references.citation: J Clin Oncol. 2008 May 1;26(13):2178-85
references.pmid: 18445842
references.citation: Mol Cancer Ther. 2006 Dec;5(12):3071-7
references.pmid: 17172409
references.citation: Nat Rev Drug Discov. 2006 Oct;5(10):835-44
references.pmid: 17016424
references.citation: Curr Opin Investig Drugs. 2007 Jun;8(6):452-6
references.pmid: 17621874
references.citation: Melanoma Res. 2001 Feb;11(1):75-81
references.pmid: 11254118
references.citation: Cancer Res. 2007 Jun 15;67(12):5814-20
references.pmid: 17575149
references.citation: Biochem Biophys Res Commun. 2008 Jun 6;370(3):509-13
references.pmid: 18402768
references.citation: Clin Cancer Res. 2008 Jan 1;14(1):230-9
references.pmid: 18172275
references.citation: Mol Cancer Ther. 2008 Sep;7(9):2876-83
references.pmid: 18790768
references.citation: Cancer Invest. 2010 May;28(4):350-6
references.pmid: 19968499
references.citation: Hematol Oncol Clin North Am. 2009 Jun;23(3):529-45, ix
references.pmid: 19464601
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2376s-2383s
references.pmid: 16609062
references.citation: PLoS One. 2009 May 27;4(5):e5717
references.pmid: 19492075
references.citation: Expert Opin Investig Drugs. 2001 Dec;10(12):2105-16
references.pmid: 11772308
references.citation: Arch Immunol Ther Exp (Warsz). 2007 Nov-Dec;55(6):363-72
references.pmid: 18060370
references.citation: Cancer Res. 2005 May 15;65(10):4005-11
references.pmid: 15899789
references.citation: Clin Cancer Res. 2009 Mar 1;15(5):1674-85
references.pmid: 19208796
references.citation: FASEB J. 2008 Apr;22(4):954-65
references.pmid: 18039929
references.citation: Oncogene. 2006 Oct 12;25(47):6262-76
references.pmid: 16702958
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2366s-2370s
references.pmid: 16609060
references.citation: Br J Dermatol. 2007 Jun;156(6):1204-13
references.pmid: 17388918
references.citation: Nature. 2005 Aug 4;436(7051):720-4
references.pmid: 16079850
references.citation: Recent Pat Anticancer Drug Discov. 2009 Jan;4(1):28-35
references.pmid: 19149686
references.citation: J Dermatol Sci. 2007 Apr;46(1):11-20
references.pmid: 17267180
references.citation: Front Biosci. 2005 Sep 01;10:2986-3001
references.pmid: 15970553
references.citation: Genes Dev. 1997 Nov 1;11(21):2822-34
references.pmid: 9353252
references.citation: Cancer Lett. 2002 May 28;179(2):133-40
references.pmid: 11888667
references.citation: CA Cancer J Clin. 2009 Jul-Aug;59(4):225-49
references.pmid: 19474385
references.citation: J Biol Chem. 2000 Sep 1;275(35):27354-9
references.pmid: 10869359
references.citation: Int J Cancer. 2003 Jun 10;105(2):165-75
references.pmid: 12673674
references.citation: Mol Cell. 2009 Nov 13;36(3):477-86
references.pmid: 19917255
references.citation: Biochim Biophys Acta. 2003 Jun 5;1653(1):25-40
references.pmid: 12781369
references.citation: Pigment Cell Melanoma Res. 2010 Feb;23(1):93-102
references.pmid: 19895547
references.citation: Mol Cancer Ther. 2010 Jan;9(1):134-44
references.pmid: 20053779
references.citation: Br J Cancer. 2006 Sep 4;95(5):581-6
references.pmid: 16880785
references.citation: Pigment Cell Melanoma Res. 2010 Apr;23(2):190-200
references.pmid: 20149136
references.citation: J Clin Oncol. 2008 May 1;26(13):2139-46
references.pmid: 18390968
references.citation: Onkologie. 2004 Dec;27(6):540-4
references.pmid: 15591712
references.citation: Clin Cancer Res. 2001 Jul;7(7):2016-21
references.pmid: 11448919
references.citation: Expert Rev Anticancer Ther. 2007 May;7(5):617-26
references.pmid: 17492926
references.citation: Nat Rev Mol Cell Biol. 2004 Nov;5(11):875-85
references.pmid: 15520807
references.citation: Cancer Res. 2006 Oct 1;66(19):9483-91
references.pmid: 17018604
references.citation: Expert Opin Emerg Drugs. 2009 Dec;14(4):633-48
references.pmid: 19715444
references.citation: J Invest Dermatol. 2008 Aug;128(8):2013-23
references.pmid: 18323781
references.citation: Nature. 1999 Jul 29;400(6743):468-72
references.pmid: 10440378
references.citation: Cancer Res. 2003 Feb 15;63(4):756-9
references.pmid: 12591721
references.citation: Pigment Cell Melanoma Res. 2009 Aug;22(4):400-19
references.pmid: 19493313
references.citation: Cancer Cell. 2004 Oct;6(4):313-9
references.pmid: 15488754
references.citation: Oncogene. 2007 May 14;26(22):3291-310
references.pmid: 17496923
references.citation: Cancer J Sci Am. 2000 Feb;6 Suppl 1:S99-103
references.pmid: 10685668
references.citation: Rev Recent Clin Trials. 2007 May;2(2):121-34
references.pmid: 18473997
references.citation: Methods Enzymol. 2008;439:25-38
references.pmid: 18374154
references.citation: Am J Pathol. 2009 Jun;174(6):2367-77
references.pmid: 19389934
references.citation: Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2371s-2375s
references.pmid: 16609061
references.citation: Neoplasia. 2009 Aug;11(8):720-31
references.pmid: 19649202
references.citation: Br J Dermatol. 2010 Mar;162(3):677-80
references.pmid: 19919630
references.citation: Cancer Chemother Pharmacol. 2008 Apr;61(4):535-48
references.pmid: 18026728
references.citation: J Natl Cancer Inst. 2003 Dec 17;95(24):1878-90
references.pmid: 14679157
references.citation: Br J Cancer. 2009 Nov 17;101(10):1724-30
references.pmid: 19861964
references.citation: Cancer Lett. 2009 Oct 8;283(2):125-34
references.pmid: 19217204
references.citation: Clin Cancer Res. 2003 Aug 15;9(9):3362-8
references.pmid: 12960123
references.citation: Prog Cell Cycle Res. 2003;5:219-24
references.pmid: 14593716
references.citation: J Invest Dermatol. 2009 Feb;129(2):383-91
references.pmid: 18754039
references.citation: J Clin Oncol. 2009 Jun 10;27(17):2823-30
references.pmid: 19349552
references.citation: J Natl Cancer Inst. 2001 May 2;93(9):678-83
references.pmid: 11333289
references.citation: Cancer Res. 2001 Jan 1;61(1):131-7
references.pmid: 11196150
references.citation: Neuro Endocrinol Lett. 2002 Jul;23 Suppl 2:48-51
references.pmid: 12163848
references.citation: J Transl Med. 2012 Dec 10;10:246
references.pmid: 23228035
references.citation: J Dtsch Dermatol Ges. 2006 Mar;4(3):205-17
references.pmid: 16626317
references.citation: Curr Top Med Chem. 2007;7(14):1364-78
references.pmid: 17692026
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Oncogene. 2004 Aug 19;23(37):6292-8
references.pmid: 15208680
references.citation: Cancer Res. 2006 Aug 15;66(16):8200-9
references.pmid: 16912199
references.citation: Pigment Cell Melanoma Res. 2009 Aug;22(4):388-99
references.pmid: 19493316
references.citation: Semin Cutan Med Surg. 2009 Jun;28(2):96-102
references.pmid: 19608060
references.citation: Cancer Res. 2000 Apr 1;60(7):1800-4
references.pmid: 10766161
references.citation: Oncogene. 2001 Nov 15;20(52):7658-67
references.pmid: 11753643
references.citation: Proc Natl Acad Sci U S A. 2009 May 12;106(19):7957-61
references.pmid: 19383798
references.citation: J Biol Chem. 2010 Jan 1;285(1):242-54
references.pmid: 19880519
references.citation: Oncogene. 2010 Apr 22;29(16):2449-56
references.pmid: 20118982
references.citation: J Invest Dermatol. 2007 Sep;127(9):2207-15
references.pmid: 17508026
references.citation: Cancer Res. 2006 Jan 15;66(2):999-1006
references.pmid: 16424035
references.citation: Oncogene. 2008 Feb 7;27(7):877-95
references.pmid: 17724477
references.citation: J Invest Dermatol. 2006 Jan;126(1):154-60
references.pmid: 16417231
references.citation: Clin Cancer Res. 2008 Aug 1;14(15):4836-42
references.pmid: 18676756
references.citation: Nature. 2010 Mar 18;464(7287):427-30
references.pmid: 20179705
references.citation: Nature. 2010 Apr 15;464(7291):1067-70
references.pmid: 20305636
references.citation: Oncology. 2000 Feb;58(2):89-95
references.pmid: 10705235
references.citation: Cancer Cell. 2009 Apr 7;15(4):294-303
references.pmid: 19345328
references.citation: Int J Oncol. 2009 Jun;34(6):1481-9
references.pmid: 19424565
references.citation: Cancer Res. 2001 Oct 15;61(20):7507-17
references.pmid: 11606387
references.citation: Am J Ther. 2003 May-Jun;10(3):203-10
references.pmid: 12756427
references.citation: Cell. 2010 Jan 22;140(2):209-21
references.pmid: 20141835
references.citation: Cancer Res. 2005 Mar 15;65(6):2412-21
references.pmid: 15781657
references.citation: Cell. 2004 Mar 19;116(6):855-67
references.pmid: 15035987
references.citation: Curr Oncol Rep. 2006 Sep;8(5):400-5
references.pmid: 16901402
references.citation: Onkologie. 2005 Feb;28(2):101-7
references.pmid: 15665559
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6
references.pmid: 18287029
references.citation: Nature. 2009 Sep 24;461(7263):542-5
references.pmid: 19727074
references.citation: J Clin Pathol. 2005 Nov;58(11):1163-9
references.pmid: 16254105
references.citation: J Invest Dermatol. 2008 Aug;128(8):2003-12
references.pmid: 18323787
references.citation: J Clin Oncol. 2005 Aug 10;23(23):5281-93
references.pmid: 16009947
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 1;106(48):20411-6
references.pmid: 19915144
references.citation: Cancer Res. 2008 Sep 15;68(18):7638-49
references.pmid: 18794153
references.citation: APMIS. 2007 Oct;115(10):1161-76
references.pmid: 18042149
references.citation: Nature. 2010 Mar 18;464(7287):431-5
references.pmid: 20130576
references.citation: Mol Cancer Ther. 2007 Aug;6(8):2209-19
references.pmid: 17699718
references.citation: Br J Cancer. 2007 Feb 12;96(3):445-9
references.pmid: 17245336
references.citation: Purinergic Signal. 2006 Nov;2(4):627-32
references.pmid: 18404465
references.citation: Cancer Cell. 2007 May;11(5):447-60
references.pmid: 17482134
references.citation: Cell. 2008 Feb 8;132(3):363-74
references.pmid: 18267069
references.citation: Cancer Res. 2008 Jan 1;68(1):5-8
references.pmid: 18172288
references.citation: Expert Rev Anticancer Ther. 2008 Apr;8(4):553-60
references.pmid: 18402522
references.citation: Cancer Cell. 2003 Aug;4(2):95-8
references.pmid: 12957284
references.citation: J Invest Dermatol. 2003 Jan;120(1):109-15
references.pmid: 12535206
references.citation: Photochem Photobiol. 2008 Mar-Apr;84(2):289-306
references.pmid: 18086245
references.citation: Semin Oncol. 2006 Aug;33(4):392-406
references.pmid: 16890795
references.citation: J Natl Cancer Inst. 2001 Jul 18;93(14):1062-74
references.pmid: 11459867
references.citation: Neoplasia. 2008 Nov;10(11):1231-9
references.pmid: 18953432
references.citation: Mol Cell Biol. 2010 Feb;30(3):806-19
references.pmid: 19933846
references.citation: Cancer Res. 2004 Oct 1;64(19):7099-109
references.pmid: 15466206
references.citation: Expert Rev Anticancer Ther. 2006 Jan;6(1):121-30
references.pmid: 16375649
references.citation: J Clin Endocrinol Metab. 2007 Dec;92(12):4712-8
references.pmid: 17878251
references.citation: Clin Cancer Res. 2008 Jun 1;14(11):3571-81
references.pmid: 18519791
references.citation: Cancer Res. 2007 Oct 15;67(20):9750-61
references.pmid: 17942905
references.citation: Expert Opin Investig Drugs. 2003 Mar;12(3):413-21
references.pmid: 12605564
references.citation: Melanoma Res. 2001 Feb;11(1):11-9
references.pmid: 11254111
references.citation: Cancer Res. 2008 May 1;68(9):3429-39
references.pmid: 18451171
references.citation: J Am Chem Soc. 2001 Mar 7;123(9):2107-8
references.pmid: 11456854
references.citation: Mol Cancer Ther. 2006 May;5(5):1136-44
references.pmid: 16731745
references.citation: Oncogene. 2009 Jan 8;28(1):85-94
references.pmid: 18794803
references.citation: Nat Genet. 2009 May;41(5):544-52
references.pmid: 19282848
references.citation: Br J Cancer. 2009 Feb 10;100(3):431-5
references.pmid: 19156138