Sensitivity Analysis of the NPM-ALK Signalling Network Reveals Important Pathways for Anaplastic Large Cell Lymphoma Combination Therapy.
A large subset of anaplastic large cell lymphoma (ALCL) patients harbour a somatic aberration in which anaplastic lymphoma kinase (ALK) is fused to nucleophosmin (NPM) resulting in a constitutively active signalling fusion protein, NPM-ALK. We computationally simulated the signalling network which mediates pathological cell survival and proliferation through NPM-ALK to identify therapeutically targetable nodes through which it may be possible to regain control of the tumourigenic process. The simulations reveal the predominant role of the VAV1-CDC42 (cell division control protein 42) pathway in NPM-ALK-driven cellular proliferation and of the Ras / mitogen-activated ERK kinase (MEK) / extracellular signal-regulated kinase (ERK) cascade in controlling cell survival. Our results also highlight the importance of a group of interleukins together with the Janus kinase 3 (JAK3) / signal transducer and activator of transcription 3 (STAT3) signalling in the development of NPM-ALK derived ALCL. Depending on the activity of JAK3 and STAT3, the system may also be sensitive to activation of protein tyrosine phosphatase-1 (SHP1), which has an inhibitory effect on cell survival and proliferation. The identification of signalling pathways active in tumourigenic processes is of fundamental importance for effective therapies. The prediction of alternative pathways that circumvent classical therapeutic targets opens the way to preventive approaches for countering the emergence of cancer resistance.
Department of Chemistry and Biomedical Sciences, Linnæus University, Kalmar, Sweden.|Linnæus University Centre for Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.|Institute of Computational Science, Faculty of Informatics, Università della Svizzera Italiana, Lugano, Switzerland.|Swiss Institute of Bioinformatics, Lausanne, Switzerland.
Antoine
A
Buetti-Dinh
Huntsman Cancer Institute, The University of Utah, Salt Lake City, United States of America.|Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, United States of America.
Thomas
T
O'Hare
Department of Chemistry and Biomedical Sciences, Linnæus University, Kalmar, Sweden.|Linnæus University Centre for Biomaterials Chemistry, Linnæus University, Kalmar, Sweden.
Ran
http://orcid.org/0000-0001-8696-3104
R
Friedman
Nat Rev Cancer. 2008 Jan;8(1):11-23
18097461
Am J Clin Pathol. 2007 May;127(5):707-22
17511113
J Hematol Oncol. 2015 Feb 27;8:17
25888090
Mol Biosyst. 2015 Aug;11(8):2238-46
26118552
Blood. 2000 Dec 1;96(12):3681-95
11090048
Cancers (Basel). 2015 Apr 30;7(2):763-83
25941796
Br J Cancer. 2012 Feb 14;106(4):763-7
22240786
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):4181-6
8633037
Sci Signal. 2015 Jan 20;8(360):ra6
25605972
Science. 1994 Mar 4;263(5151):1281-4
8122112
Science. 2003 Oct 31;302(5646):875-8
14593182
Nature. 2008 Oct 16;455(7215):971-4
18923524
Blood. 2006 Oct 15;108(8):2796-803
16825495
Nature. 2015 Sep 24;525(7570):543-7
26367798
Blood. 2004 Sep 1;104(5):1580-1
15317731
Cancer Lett. 2010 Dec 28;299(2):81-94
20934803
Nat Rev Cancer. 2002 Jul;2(7):489-501
12094235
Genome Res. 2003 Nov;13(11):2498-504
14597658
Cancer Res. 2011 Sep 15;71(18):6051-60
21791641
Mol Cell Biol. 1997 Mar;17(3):1346-53
9032261
Am J Pathol. 2001 Oct;159(4):1495-505
11583976
N Engl J Med. 2010 Oct 28;363(18):1734-9
20979473
Cancer Cell. 2015 Mar 9;27(3):397-408
25759024
Cancer Res. 2004 May 1;64(9):3256-64
15126367
Clin Cancer Res. 2003 Sep 1;9(10 Pt 1):3692-9
14506160
J Immunol. 2013 Dec 15;191(12):6200-7
24218456
PLoS One. 2013 Dec 20;8(12):e82059
24376513
Cell. 2006 Mar 24;124(6):1225-39
16564013
Mol Cell Biol. 2000 Dec;20(24):9212-24
11094073
J Hematol Oncol. 2012 Aug 01;5:43
22852872
J Natl Cancer Inst. 2014 Feb;106(2):djt378
24491302
Proc Natl Acad Sci U S A. 2013 Nov 26;110(48):19519-24
24218589
J Mol Endocrinol. 2011 Jul 04;47(1):R11-23
21502284
Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9964-9
16766651
J Hematol Oncol. 2013 Dec 05;6:90
24308725
J Biol Chem. 2002 Sep 27;277(39):35990-8
12122009
Mol Cancer Res. 2014 Jan;12 (1):111-8
24296758
Clin Cancer Res. 2008 Oct 15;14(20):6618-24
18927303
Am J Pathol. 1997 Apr;150(4):1207-11
9094977
Exp Hematol. 2003 Apr;31(4):309-15
12691918
Nat Rev Cancer. 2014 Nov;14(11):736-46
25342631
Sci Transl Med. 2012 Feb 8;4(120):120ra17
22277784
Bioorg Med Chem Lett. 2014 Oct 1;24(19):4617-21
25217444
Ther Adv Hematol. 2013 Apr;4(2):119-31
23610619
Nature. 2015 Sep 24;525(7570):538-42
26367796
Cancer Res. 2006 Sep 15;66(18):9002-8
16982741
Nature. 2008 Oct 16;455(7215):975-8
18923525
Blood. 2007 Oct 1;110(7):2259-67
17519389
Transl Lung Cancer Res. 2013 Apr;2(2):72-86
25806218
Cell. 1995 Mar 10;80(5):729-38
7889566
Mol Cell Biol. 1998 Dec;18(12):6951-61
9819383
Science. 2014 Dec 19;346(6216):1480-6
25394791
Leukemia. 2006 Sep;20(9):1602-9
16871283
Nat Med. 2005 Jun;11(6):623-9
15895073
Nature. 2008 Oct 16;455(7215):967-70
18923523
Exp Hematol. 1999 Dec;27(12):1796-805
10641597
Nature. 1992 Dec 17;360(6405):689-92
1465135
N Engl J Med. 2013 Jun 20;368(25):2385-94
23724913
Science. 1998 Jan 23;279(5350):509-14
9438836
Cancer Res. 2002 Mar 1;62(5):1559-66
11888936
Am J Transplant. 2004 Jan;4(1):51-7
14678034
N Engl J Med. 2014 Mar 27;370(13):1189-97
24670165
Proc Natl Acad Sci U S A. 2015 Sep 29;112(39):E5381-90
26372962
EMBO J. 1993 May;12(5):1929-36
8491186
Blood. 2006 May 15;107(10 ):4130-8
16469875
Cancer Sci. 2011 Feb;102(2):302-8
21205076
Cancer Cell. 2014 Aug 11;26(2):207-21
25065853
Clin Cancer Res. 2009 Sep 15;15(18):5609-14
19737948
Nature. 2000 Oct 5;407(6804):651-4
11034217
Cell. 1984 Aug;38(1):109-17
6380758
Nature. 2000 Jul 27;406(6794):378-82
10935628
Cancer Res. 2008 Nov 1;68(21):8899-907
18974134
Oncogene. 2003 Aug 21;22(35):5399-407
12934099
Cancer Cell. 2015 Apr 13;27(4):516-32
25873174
Blood. 2006 Oct 1;108(7):2407-15
16763206
Mol Biosyst. 2015 Aug;11(8):2247-54
26057862
Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39
25322323
Eur J Pharmacol. 2008 Mar 17;582(1-3):154-61
18242596
Clin Lung Cancer. 2006 Jan;7(4):273-5
16512982
Curr Biol. 1996 Dec 1;6(12):1628-33
8994827
Cancer Res. 2005 Sep 1;65(17):7628-34
16140928