Targeting the mitogen-activated protein kinase pathway: physiological feedback and drug response.
Mitogen-activated protein kinase (MAPK) pathway activation is a frequent event in human cancer and is often the result of activating mutations in the BRAF and RAS oncogenes. Targeted inhibitors of BRAF and its downstream effectors are in various stages of preclinical and clinical development. These agents offer the possibility of greater efficacy and less toxicity than current therapies for tumors driven by oncogenic mutations in the MAPK pathway. Early clinical results with the BRAF-selective inhibitor PLX4032 suggest that this strategy will prove successful in a select group of patients whose tumors are driven by V600E BRAF. Relief of physiologic feedback upon pathway inhibition may, however, attenuate drug response and contribute to the development of acquired resistance. An improved understanding of the adaptive response of cancer cells to MAPK pathway inhibition may thus aid in the identification of those patients most likely to respond to targeted pathway inhibitors and provide a rational basis for tailored combination strategies.
Pratilas
Christine A
CA
Department of Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Solit
David B
DB
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D025461:Feedback, Physiological; D011905:Genes, ras; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases
Nat Struct Mol Biol. 2004 Dec;11(12):1192-7
15543157
Cancer Metastasis Rev. 2008 Jun;27(2):253-61
18330678
Genes Dev. 1996 Nov 1;10(21):2684-95
8946910
J Clin Oncol. 2009 Jun 10;27(17):2823-30
19349552
Mol Cell. 2005 Dec 22;20(6):963-9
16364920
Am J Pathol. 2003 Jun;162(6):1807-15
12759238
J Cell Sci. 2004 Apr 15;117(Pt 10):1875-84
15090593
Mol Cancer Res. 2007 May;5(5):509-20
17510316
J Med Chem. 2008 Nov 27;51(22):7049-52
18942827
Cancer Res. 2004 Aug 15;64(16):5556-9
15313890
Cancer Res. 2006 Feb 15;66(4):2048-58
16489004
Nature. 2006 Jan 19;439(7074):358-62
16273091
Cancer Res. 2008 Aug 1;68(15):6145-53
18676837
Nat Rev Cancer. 2004 Dec;4(12):937-47
15573115
Cancer Res. 2008 Jun 15;68(12):4853-61
18559533
Cell. 1995 Dec 15;83(6):879-88
8521512
Mol Cell Biol. 1995 Oct;15(10):5214-25
7565670
Proc Natl Acad Sci U S A. 1983 Apr;80(8):2112-6
6572964
Nature. 1992 Apr 23;356(6371):713-5
1570015
Nat Rev Cancer. 2003 Jun;3(6):459-65
12778136
J Clin Invest. 2008 Sep;118(9):3065-74
18725988
Cancer Res. 2009 Sep 1;69(17):6773-81
19690147
Br J Cancer. 2006 Sep 4;95(5):581-6
16880785
Mol Cell. 2005 Jan 21;17(2):215-24
15664191
Cancer Res. 2008 Nov 15;68(22):9375-83
19010912
J Biol Chem. 1995 Nov 17;270(46):27489-94
7499206
Biochim Biophys Acta. 2007 Aug;1773(8):1248-55
17194493
Nature. 2004 Jan 15;427(6971):256-60
14724641
Genes Dev. 2002 Aug 15;16(16):2045-57
12183360
Science. 1994 Oct 7;266(5182):56-7
7939645
Br J Cancer. 2009 Nov 17;101(10):1724-30
19861964
Cancer Res. 2004 Sep 1;64(17):6127-36
15342396
Nature. 2002 Jun 27;417(6892):949-54
12068308
Science. 1999 Nov 26;286(5445):1741-4
10576742
Nature. 1982 Jun 10;297(5866):479-83
6283358
Nat Med. 1999 Jul;5(7):810-6
10395327
Nature. 2010 Mar 18;464(7287):427-30
20179705
Cancer Res. 2003 Jul 15;63(14):3955-7
12873990
Cancer Chemother Pharmacol. 2007 Apr;59(5):671-9
16944149
Cancer Res. 2007 Dec 1;67(23):11463-9
18056475
J Clin Endocrinol Metab. 2008 Jun;93(6):2194-201
18381570
Cell. 2009 May 29;137(5):835-48
19490893
Cell. 2010 Jan 22;140(2):209-21
20141835
Cell. 2004 Mar 19;116(6):855-67
15035987
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6
18287029
Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4519-24
19251651
Nature. 1993 May 6;363(6424):15-6
8479530
J Clin Oncol. 2005 Aug 10;23(23):5281-93
16009947
Curr Opin Cell Biol. 1997 Apr;9(2):174-9
9069260
Oncol Rep. 2005 Dec;14(6):1481-5
16273242
Nature. 2010 Mar 18;464(7287):431-5
20130576
Nat Rev Mol Cell Biol. 2004 Jun;5(6):441-50
15173823
Science. 1993 Jun 11;260(5114):1658-61
8503013
Proc Natl Acad Sci U S A. 1982 Jun;79(11):3637-40
6285355
Cell Signal. 2003 May;15(5):463-9
12639709
J Clin Oncol. 2004 Nov 15;22(22):4456-62
15483017
Clin Cancer Res. 2010 Apr 15;16(8):2450-7
20332327
Cancer Res. 2004 Oct 1;64(19):7099-109
15466206
Cancer Res. 2002 Dec 1;62(23):6997-7000
12460918
Nature. 1999 Sep 9;401(6749):173-7
10490027
Clin Cancer Res. 2010 Mar 15;16(6):1924-37
20215549