Although the vast majority of patients with chronic myeloid leukemia (CML) respond to the tyrosine kinase inhibitor (TKI) imatinib mesylate, resistance might occur de novo or during treatment.
Methods
The authors reviewed the known mechanisms of primary and secondary resistance to imatinib and other TKIs used in the management of CML.
Results
Mutations within the kinase domain of BCRABLI account for 30% to 40% of cases of imatinib resistance. Other mechanisms include BCRABLI amplification, overexpression of the SRC family of kinases, and pharmacokinetic and pharmacodynamic factors.
Conclusions
Although not all resistance mechanisms have been identified and understood, several agents based on the known mechanisms have already been designed and developed and are beginning clinical trials.
References
1.
NowellP.C., HungerfordD.A.. A minute chromosome in human chronic granulocytic leukemia.Science.1960; 132: 1497. Abstract.
2.
RowleyJ.D.. Letter: a new consistent chromosomal abnormality in chronic mye-logenous leukaemia identified by quinacrine fluorescence and Giemsa staining.Nature.1973; 243(5405): 290–293.
3.
BartramC.R., de KleinA., HagemeijerA.. Translocation of c-ab1 oncogene correlates with the presence of a Philadelphia chromosome in chronic myelocytic leukaemia.Nature.1983; 306(5940): 277–280.
4.
GroffenJ., StephensonJ.R., HeisterkampN.. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22.Cell.1984; 36(1): 93–99.
5.
RamarajP., SinghH., NiuN.. Effect of mutational inactivation of tyrosine kinase activity on BCR/ABL-induced abnormalities in cell growth and adhesion in human hematopoietic progenitors.Cancer Res.2004; 64(15): 5322–5331.
6.
ZhaoR.C., JiangY., VerfaillieC.M.. A model of human p210(bcr/ABL)-mediated chronic mye-logenous leukemia by transduction of primary normal human CD34(+) cells with a BCR/ABL-containing retroviral vector.Blood.2001; 97(8): 2406–2412.
7.
DaleyG.Q., Van EttenR.A., BaltimoreD.. Induction of chronic mye-logenous leukemia in mice by the P210bcr/abl gene of the Philadelphia chromosome.Science.1990; 247(4944): 824–830.
8.
KelliherM.A., McLaughlinJ., WitteO.N.. Induction of a chronic mye-logenous leukemia-like syndrome in mice with v-abl and BCR/ABL.Proc Natl Acad Sci U S A.1990; 87(17): 6649–6653.
9.
ZhangX., RenR.. BCRABL efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic mye-logenous leukemia.Blood.1998; 92(10): 3829–3840.
10.
HochhausA., DrukerB.J., LarsonR.A.. IRIS 6-year follow-up: sustained survival and declining annual rate of transformation in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib.Blood (ASH Annual Meeting Abstracts).2007; 110. Abstract 25.
11.
DrukerB.J., GuilhotF., O'BrienS.G.. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia.N Engl J Med.2006; 355(23): 2408–2417.
12.
DrukerB.J., SawyersC.L., KantarjianH.. Activity of a specific inhibitor of the BCRABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.N Engl J Med.2001; 344(14): 1038–1042. Erratum in: N Engl J Med. 2001; 345(3): 232.
13.
RenR.. Mechanisms of BCRABL in the pathogenesis of chronic mye-logenous leukaemia.Nat Rev Cancer.2005; 5(3): 172–183.
14.
DrukerB.J., TamuraS., BuchdungerE.. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of BCRABL positive cells.Nat Med.1996; 2(5): 561–566.
15.
BeranM., CaoX., EstrovZ.. Selective inhibition of cell proliferation and BCRABL phosphorylation in acute lymphoblastic leukemia cells expressing Mr 190,000 BCRABL protein by a tyrosine kinase inhibitor (CGP-57148).Clin Cancer Res.1998; 4(7): 1661–1672.
16.
Gambacorti-PasseriniC., le CoutreP., MologniL.. Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis.Blood Cells Mol Dis.1997; 23(3): 380–394.
17.
O'BrienS.G., GuilhotF., LarsonR.A.. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia.N Engl J Med.2003; 348(11): 994–1004.
18.
SaldanhaJ., SilvyM., BeaufilsN.. Characterization of a reference material for BCRABL (M-BCR) mRNA quantitation by real-time amplification assays: towards new standards for gene expression measurements.Leukemia.2007; 21(7): 1481–1487. Epub 2007 May 3.
19.
BranfordS., CrossN.C., HochhausA.. Rationale for the recommendations for harmonizing current methodology for detecting BCRABL transcripts in patients with chronic myeloid leukaemia.Leukemia.2006; 20(11): 1925–1930. Epub 2006 Sep 14.
20.
MorleyA., BartleyP., Martin-HarrisH.. DNA-based measurement of BCRABL in chronic myeloid leukemia (CML).Blood (ASH Annual Meeting Abstracts).2007; 110. Abstract 2946.
21.
BaccaraniM., SaglioG., GoldmanJ.. Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet.Blood.2006; 108(6): 1809–1820. Epub 2006 May 18.
22.
le CoutreP., KreuzerK.A., PurscheS.. Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588.Cancer Chemother Pharmacol.2004; 53(4): 313–323. Epub 2003 Dec 5.
23.
PengB., HayesM., RestaD.. Pharmacokinetics and pharmacodynamics of imatinib in a phase I trial with chronic myeloid leukemia patients.J Clin Oncol.2004; 22(5): 935–942.
24.
PicardS., TitierK., EtienneG.. Trough imatinib plasma levels are associated with both cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia.Blood.2007; 109(8): 3496–3499. Epub 2006 Dec 27.
25.
Gambacorti-PasseriniC., BarniR., le CoutreP.. Role of alpha1 acid glycoprotein in the in vivo resistance of human BCRABL(+) leukemic cells to the abl inhibitor STI571.J Natl Cancer Inst.2000; 92(20): 1641–1650.
26.
JørgensenH.G., ElliottM.A., AllanE.K.. Alpha1-acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571.Blood.2002; 99(2): 713–715.
27.
MahonF.X., DeiningerM.W., SchultheisB.. Selection and characterization of BCRABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance.Blood.2000; 96(3): 1070–1079.
28.
DaiH., MarbachP., LemaireM.. Distribution of STI-571 to the brain is limited by P-glycoprotein-mediated efflux.J Pharmacol Exp Ther.2003; 304(3): 1085–1092.
29.
MahonF.X., BellocF., LagardeV.. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models.Blood.2003; 101(6): 2368–2373.
30.
ThomasJ., WangL., ClarkR.E.. Active transport of imatinib into and out of cells: implications for drug resistance.Blood.2004; 104(12): 3739–3745. Epub 2004 Aug 17.
31.
FerraoP.T., FrostM.J., SiahS.P.. Overexpression of P-glycoprotein in K562 cells does not confer resistance to the growth inhibitory effects of imatinib (STI571) in vitro.Blood.2003; 102(13): 4499–4503. Epub 2003 Jul 24.
32.
GalimbertiS., CervettiG., GuerriniF.. Quantitative molecular monitoring of BCRABL and MDR1 transcripts in patients with chronic myeloid leukemia during Imatinib treatment.Cancer Genet Cytogenet.2005; 162(1): 57–62.
33.
ZhouS., SchuetzJ.D., BuntingK.D.. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.Nat Med.2001; 7(9): 1028–1034.
34.
JordanidesN.E., JørgensenH.G., HolyoakeT.L.. Functional ABCG2 is overexpressed on primary CML CD34+ cells and is inhibited by imatinib mesylate.Blood.2006; 108(4): 1370–1373. Epub 2006 Apr 20.
35.
CrossmanL.C., DrukerB.J., DeiningerM.W.. hOCT 1 and resistance to imatinib.Blood.2005; 106(3): 1133–1134; author reply 1134.
36.
KimD.H., SriharshaL., XuW.. Clinical relevance of a pharmaco-genetic approach using multiple candidate gene polymorphisms to predict response and resistance to imatinib mesylate therapy in chronic myeloid leukemia.Blood (ASH Annual Meeting Abstracts).2007; 110. Abstract 737.
37.
KomarovaN.L., WodarzD.. Effect of cellular quiescence on the success of targeted CML therapy.PLoS ONE.2007; 2(10): e990.
38.
MichorF., HughesT.P., IwasaY.. Dynamics of chronic myeloid leukaemia.Nature.2005; 435(7046): 1267–1270.
39.
RoederI., HornM., GlaucheI.. Dynamic modeling of imatinibtreated chronic myeloid leukemia: functional insights and clinical implications.Nat Med.2006; 12(10): 1181–1184. Epub 2006 Oct 1.
40.
HoltzM.S., FormanS.J., BhatiaR.. Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli.Leukemia.2005; 19(6): 1034–1041.
41.
HoltzM.S., SlovakM.L., ZhangF.. Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic mye-logenous leukemia through reversal of abnormally increased proliferation.Blood.2002; 99(10): 3792–3800.
42.
GrahamS.M., JørgensenH.G., AllanE.. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro.Blood.2002; 99(1): 319–325.
43.
CoplandM., HamiltonA., ElrickL.J.. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction.Blood.2006; 107(11): 4532–4539. Epub 2006 Feb 9.
44.
KonigH., HolyoakeT.L., BhatiaR.. Effective and selective inhibition of chronic myeloid leukemia primitive hematopoietic progenitors by the dual Src/Abl kinase inhibitor SKI-606.Blood.2008; 111(4): 2329–2338. Epub 2007 Dec 4.
45.
LahayeT., RiehmB., BergerU.. Response and resistance in 300 patients with BCRABL–positive leukemias treated with imatinib in a single center: a 4.5-year follow-up.Cancer.2005; 103(8): 1659–1669.
46.
JabbourE., KantarjianH., JonesD.. Frequency and clinical significance of BCRABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate.Leukemia.2006; 20(10): 1767–1773. Epub 2006 Jul 20.
47.
JohanssonB., FioretosT., MitelmanF.. Cytogenetic and molecular genetic evolution of chronic myeloid leukemia.Acta Haematol.2002; 107(2): 76–94.
48.
JenningsB.A., MillsK.I.. c-myc locus amplification and the acquisition of trisomy 8 in the evolution of chronic myeloid leukaemia.Leuk Res.1998; 22(10): 899–903.
49.
CalabrettaB., PerrottiD.. The biology of CML blast crisis.Blood.2004; 103(11): 4010–4022. Epub 2004 Feb 24.
50.
GaigerA., HennT., HörthE.. Increase of BCRABL chimeric mRNA expression in tumor cells of patients with chronic myeloid leukemia precedes disease progression.Blood.1995; 86(6): 2371–2378.
51.
WendelH.G., de StanchinaE., CeperoE.. Loss of p53 impedes the antileukemic response to BCRABL inhibition.Proc Natl Acad Sci U S A.2006; 103(19): 7444–7449. Epub 2006 May 1.
HuntlyB.J., BenchA., GreenA.R.. Double jeopardy from a single translocation: deletions of the derivative chromosome 9 in chronic myeloid leukemia.Blood.2003; 102(4): 1160–1168. Epub 2003 May 1.
54.
AbramC.L., CourtneidgeS.A.. Src family tyrosine kinases and growth factor signaling.Exp Cell Res.2000; 254(1): 1–13.
55.
StanglmaierM., WarmuthM., KleinleinI.. The interaction of the BCRABL tyrosine kinase with the Src kinase Hck is mediated by multiple binding domains.Leukemia.2003; 17(2): 283–289.
56.
Danhauser-RiedlS., WarmuthM., DrukerB.J.. Activation of Src kinases p53/56lyn and p59hck by p210bcr/abl in myeloid cells.Cancer Res.1996; 56(1): 3589–3596.
57.
HuY., LiuY., PelletierS.. Requirement of Src kinases Lyn, Hck and Fgr for BCRABL1-induced B-lymphoblastic leukemia but not chronic myeloid leukemia.Nat Genet.2004; 36(5): 453–461. Epub 2004 Apr 18.
58.
BhatiaR., HoltzM., NiuN.. Persistence of malignant hematopoietic progenitors in chronic mye-logenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment.Blood.2003; 101(12): 4701–4707. Epub 2003 Feb 6.
NosakaT., KawashimaT., MisawaK.. STAT5 as a molecular regulator of proliferation, differentiation and apoptosis in hematopoietic cells.EMBO J.1999; 18(17): 4754–4765.
61.
DaiY., RahmaniM., CoreyS.J.. A Bcr/Abl-independent, Lyndependent form of imatinib mesylate (STI-571) resistance is associated with altered expression of Bcl-2.J Biol Chem.2004; 279(33): 34227–34239. Epub 2004 Jun 2.
62.
DonatoN.J., WuJ.Y., StapleyJ.. BCRABL independence and LYN kinase overexpression in chronic mye-logenous leukemia cells selected for resistance to STI571.Blood.2003; 101(2): 690–698.
63.
DonatoN.J., WuJ.Y., StapleyJ.. Imatinib mesylate resistance through BCRABL independence in chronic mye-logenous leukemia.Cancer Res.2004; 64(2): 672–677.
64.
HofmannW.K., de VosS., ElashoffD.. Relation between resistance of Philadelphia-chromosome-positive acute lymphoblastic leukaemia to the tyrosine kinase inhibitor STI571 and gene-expression profiles: a gene-expression study.Lancet.2002; 359(9305): 481–486.
65.
WuJ., MengF., LuH.. Lyn regulates BCRABL and Gab2 tyro-sine phosphorylation and c-Cbl protein stability in imatinib-resistant chronic mye-logenous leukemia cells.Blood.2008; 111(7): 3821–3829. Epub 2008 Jan 30.
66.
GorreM.E., MohammedM., EllwoodK.. Clinical resistance to STI-571 cancer therapy caused by BCRABL gene mutation or amplification.Science.2001; 293(5531): 876–880. Epub 2001 Jun 21.
67.
HochhausA., KreilS., CorbinA.S.. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy.Leukemia.2002; 16(11): 2190–2196.
68.
BarnesD.J., PalaiologouD., PanousopoulouE.. BCRABL expression levels determine the rate of development of resistance to imatinib mesy-late in chronic myeloid leukemia.Cancer Res.2005; 65(19): 8912–8919.
69.
JamiesonC.H., AillesL.E., DyllaS.J.. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.N Engl J Med.2004; 351(7): 657–667.
70.
HochhausA., La RoséeP.. Imatinib therapy in chronic mye-logenous leukemia: strategies to avoid and overcome resistance.Leukemia.2004; 18(8): 1321–1331.
71.
ShahN.P., NicollJ.M., NagarB.. Multiple BCRABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia.Cancer Cell.2002; 2(2): 117–125.
CorbinA.S., La RoséeP., StoffregenE.P.. Several BCRABL kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib.Blood.2003; 101(11): 4611–4614. Epub 2003 Feb 6.
74.
Gambacorti-PasseriniC.B., GunbyR.H., PiazzaR.. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias.Lancet Oncol.2003; 4(2): 75–85.
75.
HughesT., BranfordS.. Molecular monitoring of BCRABL as a guide to clinical management in chronic myeloid leukaemia.Blood Rev.2006; 20(1): 29–41. Epub 2005 Mar 2.
76.
CortesJ., JabbourE., KantarjianH.. Dynamics of BCRABL kinase domain mutations in chronic myeloid leukemia after sequential treatment with multiple tyrosine kinase inhibitors.Blood.2007; 110(12): 4005–4011. Epub 2007 Sep 4.
77.
SchindlerT., BornmannW., PellicenaP.. Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.Science.2000; 289(5486): 1938–1942.
78.
NagarB., BornmannW.G., PellicenaP.. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571).Cancer Res.2002; 62(15): 4236–4243.
79.
WeisbergE., ManleyP.W., BreitensteinW.. Characterization of AMN107, a selective inhibitor of native and mutant BCRABL.Cancer Cell.2005; 7(2): 129–141.
80.
KantarjianH., GilesF., WunderleL.. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.N Engl J Med.2006; 354(24): 2542–2551.
81.
TalpazM., ShahN.P., KantarjianH.. Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias.N Engl J Med.2006; 354(24): 2531–2541.
82.
LombardoL.J., LeeF.Y., ChenP.. Discovery of N-(2-chloro-6-methyl-phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carboxamide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays.J Med Chem.2004; 47(27): 6658–6661.
83.
ShahN.P., TranC., LeeF.Y.. Overriding imatinib resistance with a novel ABL kinase inhibitor.Science.2004; 305(5682): 399–401.
84.
WeisbergE., ManleyP., MestanJ.. AMN107 (nilotinib): a novel and selective inhibitor of BCRABL.Br J Cancer.2006; 94(12): 1765–1769. Epub 2006 May 23.
85.
HantschelO., NagarB., GuettlerS.. A myristoyl/phosphotyrosine switch regulates c-Abl.Cell.2003; 112(6): 845–857.
86.
AzamM., LatekR.R., DaleyG.Q.. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCRABL.Cell.2003; 112(6): 831–843.
87.
Quintás-CardamaA., GibbonsD.L., KantarjianH.. Mutational analysis of chronic myeloid leukemia (CML) clones reveals heightened BCRABL1 genetic instability and wild-type BCRABL1 exhaustion in patients failing sequential imatinib and dasatinib therapy.Blood (ASH Annual Meeting Abstracts).2007; 110. Abstract 1938.
88.
HughesT., DeiningerM., HochhausA.. Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCRABL transcripts and kinase domain mutations and for expressing results.Blood.2006; 108(1): 28–37. Epub 2006 Mar 7.
89.
O'HareT., WaltersD.K., StoffregenE.P.. In vitro activity of BCRABL inhibitors AMN107 and BMS-354825 against clinically relevant imatinibresistant Abl kinase domain mutants.Cancer Res.2005; 65(11): 4500–4505.
90.
DeiningerM., BuchdungerE., DrukerB.J.. The development of imatinib as a therapeutic agent for chronic myeloid leukemia.Blood.2005; 105(7): 2640–2653. Epub 2004 Dec 23.
91.
CarterT.A., WodickaL.M., ShahN.P.. Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases.Proc Natl Acad Sci U S A.2005; 102(31): 11011–11016. Epub 2005 Jul 26.
92.
BranfordS., RudzkiZ., WalshS.. Detection of BCRABL mutations in patients with CML treated with imatinib is virtually always accompanied by clinical resistance, and mutations in the ATP phosphate-binding loop (P-loop) are associated with a poor prognosis.Blood.2003; 102(1): 276–283. Epub 2003 Mar 6.
93.
SoveriniS., MartinelliG., RostiG.. ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.J Clin Oncol.2005; 23(18): 4100–4109. Epub 2005 May 2.
94.
ApperleyJ.F.. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia.Lancet Oncol.2007; 8(11): 1018–1029.
95.
WeisbergE., ManleyP.W., Cowan-JacobS.W.. Second generation inhibitors of BCRABL for the treatment of imatinib-resistant chronic myeloid leukaemia.Nat Rev Cancer.2007; 7(5): 345–356.
96.
KhorashadJ.S., AnandM., MarinD.. The presence of a BCRABL mutant allele in CML does not always explain clinical resistance to imatinib.Leukemia.2006; 20(4): 658–663.
97.
SkaggsB.J., GorreM.E., RyvkinA.. Phosphorylation of the ATP-binding loop directs oncogenicity of drug-resistant BCRABL mutants.Proc Natl Acad Sci U S A.2006; 103(51): 19466–19471. Epub 2006 Dec 12.
98.
GriswoldI.J., MacPartlinM., BummT.. Kinase domain mutants of BCRABL exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib.Mol Cell Biol.2006; 26(16): 6082–6093.
DeiningerM.W., McGreeveyL., WillisS.. Detection of ABL kinase domain mutations with denaturing high-performance liquid chromatography.Leukemia.2004; 18(4): 864–871.
101.
SoveriniS., MartinelliG., AmabileM.. Denaturing-HPLC-based assay for detection of ABL mutations in chronic myeloid leukemia patients resistant to Imatinib.Clin Chem.2004; 50(7): 1205–1213. Epub 2004 Apr 23.
102.
ErnstT., ErbenP., MullerM.C.. Dynamics of BCRABL mutated clones prior to hematologic or cytogenetic resistance to imatinib.Haematologica.2008; 93(2): 186–192. Epub 2008 Jan 26.
103.
WillisS.G., LangeT., DemehriS.. High-sensitivity detection of BCRABL kinase domain mutations in imatinib-naive patients: correlation with clonal cytogenetic evolution but not response to therapy.Blood.2005; 106(6): 2128–2137. Epub 2005 May 24.
104.
NardiV., RazT., CaoX.. Quantitative monitoring by polymerase colony assay of known mutations resistant to ABL kinase inhibitors.Oncogene.2008; 27(6): 775–782. Epub 2007 Aug 6.
