A growing family: adding mutated Erbb4 as a novel cancer target.
As the upward spiral of novel cancer gene discoveries and novel molecular compounds continues to accelerate, a repetitive theme in molecular drug development remains the lack of activity of initially promising agents when given to patients in clinical trials. It is however invigorating that a few targeted agents directed against a select group of a few 'cancer gene superfamilies' have escaped this all to common fate, and have evolved into novel, clinically meaningful molecular therapy strategies. Targeting dysregulated signaling of the epidermal growth factor family of transmembrane receptors (Erbb family) has encompassed over the last decade an ever increasing role in personalized treatment approaches in an increasing number of human malignancies. Erbbs are receptor tyrosine kinases that are important regulators of several signaling pathways. Two of its family members (Erbb1/EGFR and Erbb2/HER2) have previously been shown to be somatically mutated in large fraction of human cancers. To determine if this family is somatically mutated in melanoma, its sequences were recently analyzed and one of its members, Erbb4, was found to be somatically mutated in 19% of melanoma cases. Functional analysis of seven of its mutations was shown to increase its catalytic and transformation abilities as well as providing essential survival signals. Similar to other Erbb family members, mutant Erbb4 seems to confer 'oncogene addiction' on melanoma cells, making it an attractive therapeutic target. Gaining further understanding into the oncogenic mechanism of Erbb4 may not only help in the development of targeted therapy in melanoma patients but might accelerate the acceptance of a novel taxonomy of cancer which is based on the genomic perturbations in cancer genes and cancer gene families and their response to targeted agents.
Rudloff
Udo
U
National Cancer Institute, Surgery Branch, Bethesda, MD, USA.
Samuels
Yardena
Y
D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008545:Melanoma / Q000188:drug therapy / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D057285:Precision Medicine; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics
D008024:Ligands; D047428:Protein Kinase Inhibitors; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D066247:Receptor, ErbB-4
Cancer Lett. 2003 Mar 20;192(1):67-74
12637154
BMC Cancer. 2006 Dec 06;6:278
17150109
Cancer Res. 2005 Sep 1;65(17):7591-5
16140923
N Engl J Med. 2009 Sep 3;361(10):947-57
19692680
N Engl J Med. 2005 Jul 14;353(2):123-32
16014882
Cancer J Sci Am. 2000 Feb;6 Suppl 1:S11-4
10685652
N Engl J Med. 2003 Mar 27;348(13):1201-14
12660384
Cancer Res. 2002 Oct 1;62(19):5485-8
12359757
J Clin Oncol. 2010 Mar 1;28(7):1138-44
20124182
Cancer Genet Cytogenet. 2007 Mar;173(2):107-13
17321325
N Engl J Med. 2006 Aug 10;355(6):570-80
16899777
Eur J Cancer. 2006 Jan;42(1):109-11
16324836
Nature. 2007 Mar 8;446(7132):153-8
17344846
Clin Cancer Res. 2005 Feb 15;11(4):1368-71
15746034
Proc Natl Acad Sci U S A. 2008 Mar 18;105(11):4162-7
18334649
Nature. 1987 May 28-Jun 3;327(6120):293-7
3587348
Semin Oncol. 2007 Dec;34(6):546-54
18083378
J Clin Oncol. 2008 Dec 10;26(35):5705-12
19001320
J Clin Oncol. 2005 Apr 10;23(11):2493-501
15710947
Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):839-44
16467097
Nat Rev Cancer. 2004 Mar;4(3):177-83
14993899
Cancer Res. 2006 Aug 15;66(16):8163-71
16912195
Clin Cancer Res. 2005 Apr 15;11(8):2924-9
15837743
Mol Syst Biol. 2005;1:2005.0008
16729043
Clin Cancer Res. 2006 Jul 1;12(13):3908-14
16818686
Cancer Res. 2005 Oct 1;65(19):8968-74
16204070
Clin Cancer Res. 2005 Apr 15;11(8):2879-82
15837736
J Biol Chem. 2009 Feb 27;284(9):5582-91
19098003
N Engl J Med. 2008 Oct 23;359(17):1757-65
18946061
J Clin Oncol. 2010 Mar 1;28(7):1124-30
20124187
J Clin Oncol. 2008 Sep 10;26(26):4268-75
18626007
Eur J Cancer. 2007 Feb;43(3):520-6
17224267
Am J Surg Pathol. 2006 Oct;30(10):1309-15
17001163
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4283-7
16857803
Cancer Res. 2009 Mar 1;69(5):1851-7
19223544
Curr Opin Genet Dev. 2008 Feb;18(1):73-9
18325754
J Clin Oncol. 2009 Nov 20;27(33):5620-6
19786660
Clin Cancer Res. 2007 Dec 15;13(24):7506-14
18094435
Cell Cycle. 2004 Jan;3(1):51-60
14657666
EMBO J. 1996 May 15;15(10):2452-67
8665853
J Clin Oncol. 2005 Sep 1;23(25):5900-9
16043828
Nature. 2003 Feb 13;421(6924):756-60
12610629
Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
11252954
Cancer Lett. 2006 Jun 8;237(1):89-94
16029927
Clin Cancer Res. 2005 Nov 15;11(22):8105-8
16299242
Cell. 2006 Jun 16;125(6):1137-49
16777603
PLoS One. 2007 May 09;2(5):e426
17487277
Cell. 2002 Sep 20;110(6):775-87
12297050
J Mol Med (Berl). 2006 Aug;84(8):671-81
16607561
Oncogene. 2009 Aug;28 Suppl 1:S24-31
19680293
J Clin Oncol. 2006 Sep 10;24(26):4340-6
16908931
Cell. 2002 Sep 20;110(6):763-73
12297049
Nat Genet. 2009 Oct;41(10):1127-32
19718025
Int J Cancer. 2006 Jan 1;118(1):180-4
16003726
Cancer Res. 2008 Oct 15;68(20):8322-32
18922904
Cancer Cell. 2005 Apr;7(4):287-8
15837615
Science. 2002 Aug 23;297(5585):1330-3
12154198
J Clin Oncol. 2009 Mar 20;27(9):1394-400
19224850
Science. 2006 Oct 13;314(5797):268-74
16959974
Exp Cell Res. 2009 Feb 15;315(4):649-58
18761339
J Clin Oncol. 2009 Jun 1;27(16):2622-9
19398573
Cancer Res. 2005 Mar 1;65(5):1642-6
15753357
Nature. 2009 Jan 29;457(7229):599-602
19078957
J Clin Oncol. 2005 Oct 1;23(28):6829-37
15998907
Nature. 2008 Oct 23;455(7216):1069-75
18948947
Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
15329413
Nat Rev Cancer. 2009 Jul;9(7):463-75
19536107
Oncogene. 1999 Apr 22;18(16):2607-15
10353604
Carcinogenesis. 2009 Nov;30(11):1857-64
19734198
Cancer Res. 2009 Mar 1;69(5):1966-75
19244114
N Engl J Med. 2009 Sep 3;361(10):958-67
19692684
Cancer Cell. 2004 Apr;5(4):317-28
15093539
Surg Clin North Am. 2003 Feb;83(1):1-29
12691448
J Clin Oncol. 2006 Sep 10;24(26):4228-35
16896007
Int J Cancer. 2006 Mar 15;118(6):1426-9
16187281
Anticancer Agents Med Chem. 2008 Oct;8(7):723-31
18855574
Science. 2004 Apr 23;304(5670):554
15016963
Nature. 2002 Jun 27;417(6892):949-54
12068308
Cancer. 2007 Feb 1;109(3):455-64
17200963
J Clin Oncol. 2009 Mar 10;27(8):1160-7
19204204
J Clin Oncol. 2005 Apr 10;23(11):2513-20
15738541
Cancer Cell. 2002 Aug;2(2):93-5
12204526
Mol Cell. 2003 Feb;11(2):507-17
12620237
Nature. 2004 Nov 18;432(7015):294-7
15549090
Proc Natl Acad Sci U S A. 1999 Feb 16;96(4):1415-20
9990038
Cancer Cell. 2002 Aug;2(2):127-37
12204533
Cancer Sci. 2007 Sep;98(9):1498-503
17627612
Ann Oncol. 2009 Feb;20(2):298-304
18836087
Nat Rev Cancer. 2009 Jan;9(1):28-39
19104514
Cancer Res. 1998 Aug 1;58(15):3415-22
9699674
Hum Mutat. 2007 Aug;28(8):760-70
17429853
Cancer Cell. 2006 Jul;10(1):25-38
16843263
Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20932-7
18093943
J Clin Oncol. 2009 Nov 20;27(33):5650-9
19858389
Oncogene. 2008 Jun 26;27(28):3944-56
18297114
PLoS Med. 2006 Dec;3(12):e485
17177598
Bioessays. 2007 Jun;29(6):558-65
17508401
BMC Med Genet. 2007 Sep 19;8 Suppl 1:S6
17903305
Science. 2004 Jun 4;304(5676):1497-500
15118125
Cell. 2002 May 3;109(3):275-82
12015977
Ann Oncol. 2005 Jul;16(7):1081-6
15851406
N Engl J Med. 2001 Feb 22;344(8):601-2
11207357
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6
18287029
Nature. 2007 Jan 25;445(7126):437-41
17206155
Cancer Res. 2009 Nov 1;69(21):8341-8
19826035
Cancer Res. 2008 Oct 1;68(19):8022-30
18829560
Mol Biol Cell. 2006 Jan;17(1):67-79
16251361
Mol Cancer Ther. 2007 Jan;6(1):93-100
17237269
Nature. 2005 Aug 11;436(7052):792
16094359
Lancet. 2009 Mar 28;373(9669):1097-104
19303137
Clin Cancer Res. 2005 Jun 1;11(11):4182-90
15930355
Nature. 2004 Sep 30;431(7008):525-6
15457249
J Clin Oncol. 2008 Apr 1;26(10):1742-51
18375904
Gastroenterology. 2004 Jul;127(1):294-9
15236194
Cell. 2000 Jan 7;100(1):57-70
10647931
FEBS Lett. 1999 Mar 26;447(2-3):227-31
10214951
Science. 2007 May 18;316(5827):1039-43
17463250
Cancer Treat Rev. 2009 Dec;35(8):685-91
19733440
Cancer Res. 2008 Nov 15;68(22):9221-30
19010894
Clin Cancer Res. 2008 May 1;14(9):2710-6
18451236
PLoS Med. 2005 Mar;2(3):e73
15737014
N Engl J Med. 2004 May 20;350(21):2129-39
15118073
J Clin Oncol. 2004 Apr 15;22(8):1382-8
15007088
Cancer Cell. 2007 Mar;11(3):217-27
17349580
N Engl J Med. 2007 Jan 18;356(3):217-26
17229949
Structure. 2007 Aug;15(8):942-54
17697999
Clin Cancer Res. 2009 Jul 1;15(13):4263-9
19549778
N Engl J Med. 2005 Nov 10;353(19):2012-24
16282176
Int J Cancer. 2006 Dec 15;119(12):2986-7
16998794
Exp Cell Res. 2003 Mar 10;284(1):66-77
12648466
Clin Cancer Res. 2006 Jan 1;12(1):57-61
16397024
Br J Cancer. 2007 Oct 22;97(8):1139-45
17940504
J Clin Oncol. 2008 Mar 1;26(7):1182-4; author reply 1184-6
18309959
Science. 2008 Sep 26;321(5897):1801-6
18772397
Clin Cancer Res. 2005 Aug 1;11(15):5539-48
16061871
J Clin Oncol. 2009 Apr 1;27(10):1667-74
19255323
Mol Cell Biol. 2009 Sep;29(18):4935-48
19596786
J Natl Cancer Inst. 2005 May 4;97(9):643-55
15870435
Gastroenterology. 2001 Jun;120(7):1713-9
11375952
Science. 2007 Nov 16;318(5853):1108-13
17932254