Inside life of melanoma cell signaling, molecular insights, and therapeutic targets.
Melanoma is one of the fastest growing tumor types in the United States. Immunotherapy and chemotherapy benefit only a few patients with metastatic disease. Therapy targeting a signaling pathway critical to the cancer's growth can provide dramatic benefit in several other malignancies and may be a valuable strategy for advanced melanoma, if drugs with a favorable therapeutic index are effective against essential molecular pathways. One such target is the V600E "gain-of-function" BRAF mutation found in 60% of melanomas; other mutations or molecular alterations cooperate with V600E BRAF, particularly those that cause loss of function of PTEN, upstream of Akt and mammalian target of rapamycin. Rapid development of new agents, a better understanding of the target pathways and mechanisms of resistance, and carefully designed strategies to optimize combinations and sequences of these agents, potentially with chemotherapy or immunotherapy, may ultimately have the potential to overcome the previously insurmountable obstacle of therapy resistance in melanoma.
Sosman
Jeffrey A
JA
Division of Hematology/Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, 777 Preston Research Building, 2220 Pierce Avenue, Nashville, TN 37232, USA. Jeff.sosman@vanderbilt.edu
Margolin
Kim A
KA
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases
D000970:Antineoplastic Agents; D011494:Protein Kinases; C546842:MTOR protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
Clin Cancer Res. 2008 Nov 1;14(21):6821-8
18980976
Oncogene. 1989 Nov;4(11):1363-74
2682463
J Invest Dermatol. 2004 Feb;122(2):337-41
15009714
J Clin Oncol. 2003 Dec 1;21(23):4342-9
14645423
Nat Genet. 2003 Jan;33(1):19-20
12447372
Oncogene. 2007 May 14;26(22):3291-310
17496923
Nature. 2009 Jan 29;457(7229):599-602
19078957
J Clin Oncol. 2006 Oct 10;24(29):4738-45
16966688
Clin Cancer Res. 2007 Nov 1;13(21):6344-50
17975146
Semin Oncol. 1999 Aug;26(4 Suppl 12):78-83
10482197
Nat Rev Immunol. 2002 Sep;2(9):664-74
12209135
Br J Cancer. 1993 Oct;68(4):746-50
8104462
Cancer Res. 1997 Sep 1;57(17):3660-3
9288767
Cancer Res. 2004 Oct 1;64(19):7099-109
15466206
Cancer Res. 2007 Apr 1;67(7):3127-34
17409419
Nat Med. 2004 Sep;10(9):909-15
15340416
Proc Natl Acad Sci U S A. 2006 Jun 13;103(24):9136-41
16754881
Nature. 2005 Aug 4;436(7051):720-4
16079850
Pigment Cell Res. 2006 Apr;19(2):112-24
16524427
Br J Cancer. 2006 Sep 4;95(5):581-6
16880785
J Clin Oncol. 2008 May 1;26(13):2139-46
18390968
J Clin Oncol. 2006 Sep 10;24(26):4340-6
16908931
Cancer Res. 2003 Feb 15;63(4):756-9
12591721
J Clin Oncol. 2002 Jan 1;20(1):325-34
11773186
Oncogene. 2003 May 19;22(20):3092-8
12789286
Mol Cell. 2009 Jan 30;33(2):237-47
19187764
Trends Mol Med. 2006 Sep;12(9):406-14
16899407
Drugs. 2007;67(8):1125-38
17521215
Mol Cancer Ther. 2005 Dec;4(12):2008-15
16373716
Nature. 2002 Jun 27;417(6892):949-54
12068308
Cell Cycle. 2008 Jul 1;7(13):1944-8
18604170
Clin Cancer Res. 2006 Apr 1;12(7 Pt 2):2326s-2330s
16609053
Cancer Res. 2003 Sep 1;63(17):5198-202
14500344
Cell. 2008 Feb 8;132(3):363-74
18267069
N Engl J Med. 2005 Nov 17;353(20):2135-47
16291983
J Clin Oncol. 2008 Apr 20;26(12):2046-51
18421059
J Invest Dermatol. 2004 Feb;122(2):342-8
15009715
Oncogene. 2009 Jan 8;28(1):85-94
18794803