The discovery of the Src oncogene was the first step on a long journey toward improved cancer chemotherapy. In this review, we explore Src and BCR-ABL, signal transduction, and recent advances in oncogene addiction and celebrate Hidesaboro Hanafusa and the many researchers who ushered in the age of target-directed therapy against tyrosine kinase oncoproteins.
Rous P.A sarcoma of the fowl transmissible by an agent separable from the tumor cells.J Exp Med. 1911;13:397-411
2.
Martin G.The hunting of the src.Nat Rev Mol Cell Biol. 2001;2:467-75
3.
Martin GS.The road to src.Oncogene. 2004;23:7910-7
4.
Vogt PK.Oncogenes and the revolution in cancer research: homage to Hidesaburo Hanafusa (1929-2009).Genes Cancer. 2010;1:6-11
5.
Rubin H,Vogt PK.An avian leukosis virus associated with stocks of Rous sarcoma virus.Virology. 1962;17:184-94
6.
Hanafusa H,Hanafusa T,Rubin H.The defectiveness of Rous sarcoma virus.Proc Natl Acad Sci U S A. 1963;49:572-80
7.
Wang LH,Duesberg PH,Kawai S,Hanafusa H.Location of envelope-specific and sarcoma-specific oligonucleotides on RNA of Schmidt-Ruppin Rous sarcoma virus.Proc Natl Acad Sci U S A. 1976;73:447-51
8.
Duesberg PH,Vogt PK.Differences between the ribonucleic acids of transforming and nontransforming avian tumor viruses.Proc Natl Acad Sci U S A. 1970;67:1673-80
9.
Martin GS.Rous sarcoma virus: a function required for the maintenance of the transformed state.Nature. 1970;227:1021-3
10.
Stehelin D,Varmus HE,Bishop JM,Vogt PK.DNA related to the transforming gene(s) of avian sarcoma viruses is present in normal avian DNA.Nature. 1976;260:170-3
11.
Hanafusa H,Halpern CC,Buchhagen DL,Kawai S.Recovery of avian sarcoma virus from tumors induced by transformation-defective mutants.J Exp Med. 1977;146:1735-47
12.
Wang LH,Halpern CC,Nadel M,Hanafusa H.Recombination between viral and cellular sequences generates transforming sarcoma virus.Proc Natl Acad Sci U S A. 1978;75:5812-6
13.
Takeya T,Hanafusa H.Structure and sequence of the cellular gene homologous to the RSV src gene and the mechanism for generating the transforming virus.Cell. 1983;32:881-90
14.
Shalloway D,Zelenetz AD,Cooper GM.Molecular cloning and characterization of the chicken gene homologous to the transforming gene of Rous sarcoma virus.Cell. 1981;24:531-41
15.
Mayer BJ,Hamaguchi M,Hanafusa H.A novel viral oncogene with structural similarity to phospholipase C.Nature. 1988;332:272-5
16.
Shibuya M,Hanafusa H,Balduzzi PC.Cellular sequences related to three new onc genes of avian sarcoma virus (fps, yes, and ros) and their expression in normal and transformed cells.J Virol. 1982;42:143-52
17.
Groffen J,Heisterkamp N,Shibuya M,Hanafusa H,Stephenson JR.Transforming genes of avian (v-fps) and mammalian (v-fes) retroviruses correspond to a common cellular locus.Virology. 1983;125:480-6
18.
Foster DA,Levy JB,Daley GQ,Simon MC,Hanafusa H.Isolation of chicken cellular DNA sequences with homology to the region of viral oncogenes that encodes the tyrosine kinase domain.Mol Cell Biol. 1986;6:325-31
19.
Sadowski I,Stone JC,Pawson T.A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus p130gag-fps.Mol Cell Biol. 1986;6:4396-408
20.
Stone JC,Atkinson T,Smith M,Pawson T.Identification of functional regions in the transforming protein of Fujinami sarcoma virus by in-phase insertion mutagenesis.Cell. 1984;37:549-58
21.
Eckhart W,Hutchinson MA,Hunter T.An activity phosphorylating tyrosine in polyoma T antigen immunoprecipitates.Cell. 1979;18:925-33
22.
Ren R,Mayer BJ,Cicchetti P,Baltimore D.Identification of a ten-amino acid proline-rich SH3 binding site.Science. 1993;259:1157-61
23.
Lowell CA,Soriano P.Knockouts of Src-family kinases: stiff bones, wimpy T cells, and bad memories.Genes Dev. 1996;10:1845-57
24.
Brown MT,Cooper JA.Regulation, substrates and functions of src.Biochim Biophys Acta. 1996;1287:121-49
25.
Abelson HT,Rabstein LS.Lymphosarcoma: virus-induced thymic-independent disease in mice.Cancer Res. 1970;30:2213-22
26.
Nowell P,Hungerford D.A minute chromosome in human chronic granulocytic leukemia.Science. 1960;132:1497-501
27.
Rowley JD.Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining.Nature. 1973;243:290-3
28.
Shields A,Goff S,Paskind M,Otto G,Baltimore D.Structure of the Abelson murine leukemia virus genome.Cell. 1979;18:955-62
29.
Goff SP,Gilboa E,Witte ON,Baltimore D.Structure of the Abelson murine leukemia virus genome and the homologous cellular gene: studies with cloned viral DNA.Cell. 1980;22:777-85
30.
Reddy EP,Smith MJ,Srinivasan A.Nucleotide sequence of Abelson murine leukemia virus genome: structural similarity of its transforming gene product to other onc gene products with tyrosine-specific kinase activity.Proc Natl Acad Sci U S A. 1983;80:3623-7
31.
Voncken JW,Kaartinen V,Pattengale PK,Germeraad WT,Groffen J,Heisterkamp N.BCR/ABL P210 and P190 cause distinct leukemia in transgenic mice.Blood. 1995;86:4603-11
32.
Daley GQ,Van Etten RA,Baltimore D.Induction of chronic myelogenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome.Science. 1990;247:824-30
Kelly LM,Gilliland DG.Genetics of myeloid leukemias.Annu Rev Genomics Hum Genet. 2002;3:179-98
35.
Fröhling S,Döhner H.Chromosomal abnormalities in cancer.N Engl J Med. 2008;359:722-34
36.
Harrison SC.Variation on an src-like theme.Cell. 2003;112:737-40
37.
Xu W,Harrison SC,Eck MJ.Three-dimensional structure of the tyrosine kinase c-src.Nature. 1997;385:595-602
38.
Waksman G,Shoelson SE,Pant N,Cowburn D,Kuriyan J.Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: crystal structures of the complexed and peptide-free forms.Cell. 1993;72:779-90
39.
Wang J.Controlling Abl: auto-inhibition and co-inhibition?.Nat Cell Biol. 2004;6:3-7
40.
Hantschel O,Superti-Furga G.Regulation of the c-Abl and Bcr-Abl tyrosine kinases.Nat Rev Mol Cell Biol. 2004;5:33-44
41.
Zhang X,Subrahmanyam R,Wong R,Gross AW,Ren R.The NH(2)-terminal coiled-coil domain and tyrosine 177 play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl.Mol Cell Biol. 2001;21:840-53
42.
Pendergast A.The Abl family kinases: mechanisms of regulation and signaling.Adv Cancer Res. 2002;85:51-100
43.
Van Etten RA,Jackson PK,Baltimore D,Sanders MC,Matsudaira PT,Janmey PA.The COOH terminus of the c-Abl tyrosine kinase contains distinct F- and G-actin binding domains with bundling activity.J Cell Biol. 1994;124:325-40
44.
Van Etten RA,Jackson P,Baltimore D.The mouse type IV c-abl gene product is a nuclear protein, and activation of transforming ability is associated with cytoplasmic localization.Cell. 1989;58:669-78
45.
Mcwhirter JR,Wang JY.An actin-binding function contributes to transformation by the Bcr-Abl oncoprotein of Philadelphia chromosome-positive human leukemias.EMBO J. 1993;12:1533-46
46.
Li S.Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia.Leuk Lymphoma. 2008;49:19-26
47.
Li S.Src kinase signaling in leukaemia.Int J Biochem Cell Biol. 2007;39:1483-8
48.
Hu Y,Liu Y,Pelletier S, et al.Requirement of Src kinases Lyn, Hck and Fgr for BCR-ABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia.Nat Genet. 2004;36:453-61
49.
Warmuth M,Bergmann M,Priess A,Häuslmann K,Emmerich B,Hallek M.The Src family kinase Hck interacts with Bcr-Abl by a kinase-independent mechanism and phosphorylates the Grb2-binding site of Bcr.J Biol Chem. 1997;272:33260-70
50.
Danhauser-Riedl S,Warmuth M,Druker BJ,Emmerich B,Hallek M.Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells.Cancer Res. 1996;56:3589-96
51.
Lionberger JM,Wilson MB,Smithgall TE.Transformation of myeloid leukemia cells to cytokine independence by Bcr-Abl is suppressed by kinase-defective Hck.J Biol Chem. 2000;275:18581-5
52.
Klejman A,Schreiner SJ,Nieborowska-Skorska M, et al.The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells.EMBO J. 2002;21:5766-74
53.
Ptasznik A,Nakata Y,Kalota A,Emerson SG,Gewirtz AM.Short interfering RNA (siRNA) targeting the Lyn kinase induces apoptosis in primary, and drug-resistant, BCR-ABL1(+) leukemia cells.Nat Med. 2004;10:1187-9
54.
Donato NJ,Wu JY,Stapley J, et al.BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571.Blood. 2003;101:690-8
55.
Dai Y,Rahmani M,Corey SJ,Dent P,Grant S.A Bcr/Abl-independent, Lyn-dependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2.J Biol Chem. 2004;279:34227-39
56.
Azam M,Latek RR,Daley GQ.Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL.Cell. 2003;112:831-43
57.
Titz B,Low T,Komisopoulou E,Chen SS,Rubbi L,Graeber TG.The proximal signaling network of the BCR-ABL1 oncogene shows a modular organization.Oncogene. 2010;29:5895-910
58.
Pawson T.Dynamic control of signaling by modular adaptor proteins.Curr Opin Cell Biol. 2007;19:112-6
59.
Akagi T,Murata K,Shishido T,Hanafusa H.v-Crk activates the phosphoinositide 3-kinase/AKT pathway by utilizing focal adhesion kinase and H-Ras.Mol Cell Biol. 2002;22:7015-23
60.
Akagi T,Shishido T,Murata K,Hanafusa H.v-Crk activates the phosphoinositide 3-kinase/AKT pathway in transformation.Proc Natl Acad Sci U S A. 2000;97:7290-5
61.
Seo J-H,Wood LJ,Agarwal A, et al.A specific need for CRKL in p210BCR-ABL-induced transformation of mouse hematopoietic progenitors.Cancer Res. 2010;70:7325-35
62.
Hemmeryckx B,Reichert A,Watanabe M, et al.BCR/ABL P190 transgenic mice develop leukemia in the absence of Crkl.Oncogene. 2002;21:3225-31
63.
Goga A,Mclaughlin J,Afar DE,Saffran DC,Witte ON.Alternative signals to RAS for hematopoietic transformation by the BCR-ABL oncogene.Cell. 1995;82:981-8
64.
Hoover RR,Gerlach MJ,Koh EY,Daley GQ.Cooperative and redundant effects of STAT5 and Ras signaling in BCR/ABL transformed hematopoietic cells.Oncogene. 2001;20:5826-35
65.
Hu Y,Swerdlow S,Duffy TM,Weinmann R,Lee FY,Li S.Targeting multiple kinase pathways in leukemic progenitors and stem cells is essential for improved treatment of Ph+ leukemia in mice.Proc Natl Acad Sci U S A. 2006;103:16870-5
66.
Kharas MG.Abl oncogenes and phosphoinositide 3-kinase: mechanism of activation and downstream effectors.Cancer Res. 2005;65:2047-53
67.
Sonoyama J,Matsumura I,Ezoe S, et al.Functional cooperation among Ras, STAT5, and phosphatidylinositol 3-kinase is required for full oncogenic activities of BCR/ABL in K562 cells.J Biol Chem. 2002;277:8076-82
68.
Geary CG.The story of chronic myeloid leukaemia.Br J Haematol. 2000;110:2-11
69.
Wintrobe MM,Huguley CM.Nitrogen mustard as a therapeutic agent for Hodgkin’s disease, lymphosarcoma and leukemia.Ann Intern Med. 1947;27:529-40
Druker BJ.Translation of the Philadelphia chromosome into therapy for CML.Blood. 2008;112:4808-17
72.
Druker BJ.Perspectives on the development of imatinib and the future of cancer research.Nat Med. 2009;15:1149-52
73.
Gambacorti-Passerini C,Le Coutre P,Mologni L, et al.Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis.Blood Cells Mol Dis. 1997;23:380-94
74.
Deininger MW,Goldman JM,Lydon N,Melo JV.The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells.Blood. 1997;90:3691-8
75.
Druker BJ,Tamura S,Buchdunger E, et al.Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.Nat Med. 1996;2:561-6
76.
Schindler T,Bornmann W,Pellicena P,Miller WT,Clarkson B,Kuriyan J.Structural mechanism for STI-571 inhibition of Abelson tyrosine kinase.Science. 2000;289:1938-42
77.
Druker BJ,Guilhot F,O’Brien SG, et al.Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.N Engl J Med. 2006;355:2408-17
78.
Hochhaus A,O’Brien SG,Guilhot F, et al.Six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myeloid leukemia.Leukemia. 2009;23:1054-61
79.
Blanke CD,Rankin C,Demetri GD, et al.Phase III randomized, intergroup trial assessing imatinib mesylate at two dose levels in patients with unresectable or metastatic gastrointestinal stromal tumors expressing the kit receptor tyrosine kinase: S0033.J Clin Oncol. 2008;26:626-32
80.
Cools J,Deangelo DJ,Gotlib J, et al.A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.N Engl J Med. 2003;348:1201-14
81.
Gorre ME,Mohammed M,Ellwood K, et al.Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification.Science. 2001;293:876-80
82.
Kantarjian HM,Giles FJ,Bhalla KN, et al.Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results.Blood. 2011;117:1141-5
83.
O’Hare T,Deininger MW,Eide CA,Clackson T,Druker BJ.Targeting the BCR-ABL signaling pathway in therapy-resistant Philadelphia chromosome-positive leukemia.Clin Cancer Res. 2011;17:212-21
84.
O’Hare T,Walters DK,Stoffregen EP, et al.In vitro activity of Bcr-Abl inhibitors AMN107 and BMS-354825 against clinically relevant imatinib-resistant Abl kinase domain mutants.Cancer Res. 2005;65:4500-5
85.
Mayer EL,Krop IE.Advances in targeting SRC in the treatment of breast cancer and other solid malignancies.Clin Cancer Res. 2010;16:3526-32
86.
Azam M,Seeliger MA,Gray NS,Kuriyan J,Daley GQ.Activation of tyrosine kinases by mutation of the gatekeeper threonine.Nat Struct Mol Biol. 2008;15:1109-18
87.
O’Hare T,Shakespeare WC,Zhu X, et al.AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance.Cancer Cell. 2009;16:401-12
88.
Weisberg E,Choi HG,Ray A, et al.Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants.Blood. 2010;115:4206-16
89.
Zhang J,Adrián FJ,Jahnke W, et al.Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.Nature. 2010;463:501-6
Weinstein IB.Cancer. Addiction to oncogenes: the Achilles heal of cancer.Science. 2002;297:63-4
93.
Sharma SV.“Oncogenic shock”: explaining oncogene addiction through differential signal attenuation.Clin Cancer Res. 2006;12:4392S-5S
94.
Sawyers CL.Shifting paradigms: the seeds of oncogene addiction.Nat Med. 2009;15:1158-61
95.
Cooper S,Giles FJ,Savona MR.Overcoming resistance in chronic myelogenous leukemia.Leuk Lymphoma. 2009;50:1785-93
96.
Sharma SV,Settleman J.Oncogene addiction: setting the stage for molecularly targeted cancer therapy.Genes Dev. 2007;21:3214-31
97.
Corbin AS,Agarwal A,Loriaux M,Cortes J,Deininger MW,Druker BJ.Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR-ABL activity.J Clin Invest. 2011;121:396-409
98.
D’Cruz CM,Gunther EJ,Boxer RB, et al.c-MYC induces mammary tumorigenesis by means of a preferred pathway involving spontaneous Kras2 mutations.Nat Med. 2001;7:235-9
99.
Jonkers J,Berns A.Oncogene addiction: sometimes a temporary slavery.Cancer Cell. 2004;6:535-8
100.
Schlabach MR,Luo J,Solimini NL, et al.Cancer proliferation gene discovery through functional genomics.Science. 2008;319:620-4
101.
Luo B,Cheung HW,Subramanian A, et al.Highly parallel identification of essential genes in cancer cells.Proc Natl Acad Sci U S A. 2008;105:20380-5
102.
Barbie DA,Tamayo P,Boehm JS, et al.Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1.Nature. 2009;462:108-12
103.
Luo J,Emanuele MJ,Li D, et al.A genome-wide RNAi screen identifies multiple synthetic lethal interactions with the Ras oncogene.Cell. 2009;137:835-48
104.
Solimini NL,Luo J,Elledge SJ.Non-oncogene addiction and the stress phenotype of cancer cells.Cell. 2007;130:986-8
105.
Scholl C,Fröhling S,Dunn IF, et al.Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells.Cell. 2009;137:821-34
106.
Rosenbauer F,Tenen DG.Transcription factors in myeloid development: balancing differentiation with transformation.Nat Rev Immunol. 2007;7:105-17
107.
Tenen DG.Disruption of differentiation in human cancer: AML shows the way.Nat Rev Cancer. 2003;3:89-101
108.
Ito T,Kwon HY,Zimdahl B, et al.Regulation of myeloid leukaemia by the cell-fate determinant Musashi.Nature. 2010;466:765-8
109.
Kharas MG,Lengner CJ,Al-Shahrour F, et al.Musashi-2 regulates normal hematopoiesis and promotes aggressive myeloid leukemia.Nat Med. 2010;16:903-8