Mechanisms and novel approaches in overriding tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Expert Review of Anticancer Therapy

Volumn 12, Issue 3, 2012, Pages 381-392

  Karvela, Maria ^a   Helgason, G Vignir ^a   Holyoake, Tessa L ^a  

^a UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

BCR ABL; CML; drug resistance; kinase domain; leukemia; leukemic stem cell; mutation; Philadelphia chromosome; T315I; tyrosine kinase inhibitor

Indexed keywords

2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; ALISERTIB; ANTINEOPLASTIC AGENT; BAFETINIB; BMS 833923; BOSUTINIB; CANCER VACCINE; DASATINIB; DCC 2036; EVEROLIMUS; GANETESPIB; GELDANAMYCIN; GNF 5; HOMOHARRINGTONINE; HYDROXYCHLOROQUINE; IMATINIB; KW 2449; NILOTINIB; NOVOBIOCIN; OSI 027; PANOBINOSTAT; PONATINIB; PROTEIN TYROSINE KINASE INHIBITOR; RAPAMYCIN; UNCLASSIFIED DRUG; XL 228; ZILEUTON;

ANTINEOPLASTIC ACTIVITY; APOPTOSIS; CANCER COMBINATION CHEMOTHERAPY; CANCER INHIBITION; CANCER RESISTANCE; CANCER STEM CELL; CARCINOGENICITY; CHRONIC MYELOID LEUKEMIA; CLONAL EVOLUTION; CYTOGENETICS; DNA MODIFICATION; DOSE RESPONSE; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG DOSE INCREASE; DRUG EFFICACY; DRUG MECHANISM; DRUG METABOLISM; DRUG PROTEIN BINDING; DRUG SAFETY; FRAMESHIFT MUTATION; GENE ACTIVATION; GENE OVEREXPRESSION; GENOMIC INSTABILITY; HUMAN; MUTATIONAL ANALYSIS; NONHUMAN; ONCOGENE; PATIENT COMPLIANCE; REVIEW; SIGNAL TRANSDUCTION;

CLINICAL TRIALS AS TOPIC; DISEASE MANAGEMENT; DRUG RESISTANCE, NEOPLASM; FUSION PROTEINS, BCR-ABL; GENOMIC INSTABILITY; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MYELOID CELLS; PIPERAZINES; PLURIPOTENT STEM CELLS; PROTEIN KINASE INHIBITORS; PYRIMIDINES; THERAPIES, INVESTIGATIONAL; TREATMENT OUTCOME;

EID: 84857823194     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/era.12.10     Document Type: Review

References (96)

1. Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J. Natl Cancer Inst. 25, 85-109 (1960).
2. Rowley JD. Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature 243(5405), 290-293 (1973).
3. Daley GQ, Van Etten RA, Baltimore D. Induction of chronic myelogenous leukemia in mice by the p210BCR/ABL gene of the Philadelphia chromosome. Science 247(4944), 824-830 (1990).
4. Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood 105(7), 2640-2653 (2005).
5. Quintas-Cardama A, Kantarjian HM, Cortes JE. Mechanisms of primary and secondary resistance to imatinib in chronic myeloid leukemia. Cancer Control 16(2), 122-131 (2009).
6. O'Brien SG, Guilhot F, Larson Ra et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 348(11), 994-1004 (2003).
7. 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 23(6), 1054-1061 (2009).
8. Arora M, Weisdorf DJ, Spellman SR et al. HLA-identical sibling compared with 8/8 matched and mismatched unrelated donor bone marrow transplant for chronic phase chronic myeloid leukemia. J. Clin. Oncol. 27(10), 1644-1652 (2009).
9. Gambacorti-Passerini C, Antolini L, Mahon FX et al. Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib. J. Natl Cancer Inst. 103(7), 553-561 (2011).
10. Baccarani M, Castagnetti F, Gugliotta G, Palandri F, Soverini S. Response definitions and European LeukemiaNet management recommendations. Best Pract. Res. Clin. Haematol. 22(3), 331-341 (2009).
11. Kantarjian H, Cortes J. BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia: Using guidelines to make rational treatment choices. J. Natl Compr. Canc. Netw. 6(Suppl. 2), S37-S42; quiz S43-S44 (2008).
12. Perrotti D, Jamieson C, Goldman J, Skorski T. Chronic myeloid leukemia: Mechanisms of blastic transformation. J. Clin. Invest. 120(7), 2254-2264 (2010).
13. Baccarani M, Saglio G, Goldman J et al. Evolving concepts in the management of chronic myeloid leukemia: Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 108(6), 1809-1820 (2006).
14. Alvarado Y, Kantarjian H, O'Brien S et al. Significance of suboptimal response to imatinib, as defined by the European LeukemiaNet, in the long-term outcome of patients with early chronic myeloid leukemia in chronic phase. Cancer 115(16), 3709-3718 (2009).
15. Saglio G, Fava C. Practical monitoring of chronic myelogenous leukemia: When to change treatment. J. Natl Compr. Canc. Netw. 10(1), 121-129 (2012).
16. Talpaz M, Silver RT, Druker BJ et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: Results of a Phase 2 study. Blood 99(6), 1928-1937 (2002).
17. Stoklosa T, Poplawski T, Koptyra M et al. BCR/ABL inhibits mismatch repair to protect from apoptosis and induce point mutations. Cancer Res. 68(8), 2576-2580 (2008).
18. Gorre ME, Mohammed M, Ellwood K et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 293(5531), 876-880 (2001).
19. Cortes J, Deininger M. Chronic Myeloid Leukaemia. Informa Healthcare USA, Inc, NY, USA (2007).
20. Mahon FX, Deininger MW, Schultheis B et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: Diverse mechanisms of resistance. Blood 96(3), 1070-1079 (2000).
21. Hochhaus A, Kreil S, Corbin AS et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia 16(11), 2190-2196 (2002).
22. Tang C, Schafranek L, Watkins DB et al. Tyrosine kinase inhibitor resistance in chronic myeloid leukemia cell lines: Investigating resistance pathways. Leuk. Lymphoma 52(11), 2139-2147 (2011).
23. Abrahamsson AE, Geron I, Gotlib J et al. Glycogen synthase kinase 3 beta missplicing contributes to leukemia stem cell generation. Proc. Natl Acad. Sci. USA 106(10), 3925-3929 (2009).
24. Jamieson CH, Ailles LE, Dylla SJ et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351(7), 657-667 (2004).
25. Gambacorti-Passerini C, Zucchetti M, Russo D et al. Alpha1 acid glycoprotein binds to imatinib (STI571) and substantially alters its pharmacokinetics in chronic myeloid leukemia patients. Clin. Cancer Res. 9(2), 625-632 (2003).
26. Gambacorti-Passerini CB, Gunby RH, Piazza R, Galietta A, Rostagno R, Scapozza L. Molecular mechanisms of resistance to imatinib in Philadelphia-chromosome-positive leukaemias. Lancet Oncol. 4(2), 75-85 (2003).
27. Jorgensen HG, Elliott MA, Allan EK, Carr CE, Holyoake TL, Smith KD. Alpha1-acid glycoprotein expressed in the plasma of chronic myeloid leukemia patients does not mediate significant in vitro resistance to STI571. Blood 99(2), 713-715 (2002).
28. Green H, Skoglund K, Rommel F, Mirghani RA, Lotfi K. CYP3A activity influences imatinib response in patients with chronic myeloid leukemia: A pilot study on in vivo CYP3A activity. Eur. J. Clin. Pharmacol. 66(4), 383-386 (2010).
29. Mahon FX, Belloc F, Lagarde V et al. MDR1 gene overexpression confers resistance to imatinib mesylate in leukemia cell line models. Blood 101(6), 2368-2373 (2003).
30. Hatziieremia S, Jordanides NE, Holyoake TL, Mountford JC, Jorgensen HG. Inhibition of MDR1 does not sensitize primitive chronic myeloid leukemia CD34+ cells to imatinib. Exp. Hematol. 37(6), 692-700 (2009).
31. White DL, Saunders VA, Dang P et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: Higher doses of imatinib may overcome the negative impact of low OCT-1 activity. Blood 110(12), 4064-4072 (2007).
32. Noens L, Van Lierde MA, De Bock R et al. Prevalence, determinants, and outcomes of nonadherence to imatinib therapy in patients with chronic myeloid leukemia: The ADAGIO study. Blood 113(22), 5401-5411 (2009).
33. Marin D, Bazeos A, Mahon FX et al. Adherence is the critical factor for achieving molecular responses in patients with chronic myeloid leukemia who achieve complete cytogenetic responses on imatinib. J. Clin. Oncol. 28(14), 2381-2388 (2010).
34. Fioretos T, Strombeck B, Sandberg T et al. Isochromosome 17q in blast crisis of chronic myeloid leukemia and in other hematologic malignancies is the result of clustered breakpoints in 17p11 and is not associated with coding TP53 mutations. Blood 94(1), 225-232 (1999).
35. Schutte J, Opalka B, Becher R et al. Analysis of the p53 gene in patients with isochromosome 17q and Ph1-positive or -negative myeloid leukemia. Leuk. Res. 17(6), 533-539 (1993).
36. Helgason GV, Karvela M, Holyoake TL. Kill one bird with two stones: Potential efficacy of BCR-ABL and autophagy inhibition in CML. Blood 118(8), 2035-2043 (2011).
37. Warsch W, Kollmann K, Eckelhart E et al. High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia. Blood 117(12), 3409-3420 (2011).
38. Okabe S, Tauchi T, Tanaka Y, Ohyashiki K. Dasatinib preferentially induces apoptosis by inhibiting Lyn kinase in nilotinib-resistant chronic myeloid leukemia cell line. J. Hematol. Oncol. 4(1), 32 (2011).
39. 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 101(2), 690-698 (2003).
40. Nishioka C, Ikezoe T, Yang J, Yokoyama A. Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene. Leukemia 24(9), 1631-1640 (2010).
41. De Lavallade H, Finetti P, Carbuccia N et al. A gene expression signature of primary resistance to imatinib in chronic myeloid leukemia. Leuk. Res. 34(2), 254-257 (2010).
42. Carette JE, Pruszak J, Varadarajan M et al. Generation of iPSCs from cultured human malignant cells. Blood 115(20), 4039-4042 (2010).
43. Brusa G, Zuffa E, Mancini M et al. P210 BCR-ABL tyrosine kinase interaction with histone deacetylase 1 modifies histone H4 acetylation and chromatin structure of chronic myeloid leukaemia haematopoietic progenitors. Br. J. Haematol. 132(3), 359-369 (2006).
44. Lee SM, Bae JH, Kim MJ et al. BCR-ABL-independent imatinib-resistant K562 cells show aberrant protein acetylation and increased sensitivity to histone deacetylase inhibitors. J. Pharmacol. Exp. Ther. 322(3), 1084-1092 (2007).
45. Zhang B, Strauss AC, Chu S et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 17(5), 427-442 (2010).
46. Elrick LJ, Jorgensen HG, Mountford JC, Holyoake TL. Punish the parent not the progeny. Blood 105(5), 1862-1866 (2005).
47. Holtz MS, Forman SJ, Bhatia R. Nonproliferating CML CD34+ progenitors are resistant to apoptosis induced by a wide range of proapoptotic stimuli. Leukemia 19(6), 1034-1041 (2005).
48. Graham SM, Jorgensen HG, Allan E et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99(1), 319-325 (2002).
49. Mahon FX, Rea D, Guilhot J et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 11(11), 1029-1035 (2010).
50. Ross DM, Branford S, Seymour JF et al. Patients with chronic myeloid leukemia who maintain a complete molecular response after stopping imatinib treatment have evidence of persistent leukemia by DNA PCR. Leukemia 24(10), 1719-1724 (2010).
51. 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. 121(1), 396-409 (2011).
52. Ito K, Bernardi R, Morotti A et al. PML targeting eradicates quiescent leukaemia-initiating cells. Nature 453(7198), 1072-1078 (2008).
53. Naka K, Hoshii T, Muraguchi T et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 463(7281), 676-680 (2010).
54. Pellicano F, Holyoake TL. Assembling defenses against therapy-resistant leukemic stem cells: Bcl6 joins the ranks. J. Exp. Med. 208(11), 2155-2158 (2011).
55. Zhao C, Chen A, Jamieson CH et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458(7239), 776-779 (2009).
56. Scott MT, Mccaig AM, Holyoake TL. Hematology education - the education program for the annual congress of the European Hematology Association. EHA 5(1), 112-119 (2011).
57. Kantarjian HM, Talpaz M, O'Brien S et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood 101(2), 473-475 (2003).
58. Jabbour E, Kantarjian HM, Jones D et al. Imatinib mesylate dose escalation is associated with durable responses in patients with chronic myeloid leukemia after cytogenetic failure on standard-dose imatinib therapy. Blood 113(10), 2154-2160 (2009).
59. Lombardo LJ, Lee FY, Chen P et al. 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. 47(27), 6658-6661 (2004).
60. Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science 305(5682), 399-401 (2004).
61. Kantarjian H, Shah NP, Hochhaus A et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N. Engl. J. Med. 362(24), 2260-2270 (2010).
62. Cortes J, Kim DW, Raffoux E et al. Efficacy and safety of dasatinib in imatinib-resistant or -intolerant patients with chronic myeloid leukemia in blast phase. Leukemia 22(12), 2176-2183 (2008).
63. Apperley JF, Cortes JE, Kim DW et al. Dasatinib in the treatment of chronic myeloid leukemia in accelerated phase after imatinib failure: The START a trial. J. Clin. Oncol. 27(21), 3472-3479 (2009).
64. Copland M, Hamilton A, Elrick LJ et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 107(11), 4532-4539 (2006).
65. O'Hare T, Walters DK, Deininger MW, Druker BJ. AMN107: Tightening the grip of imatinib. Cancer Cell 7(2), 117-119 (2005).
66. Weisberg E, Manley PW, Breitenstein W et al. Characterization of AMN107, a selective inhibitor of native and mutant BCR-ABL. Cancer Cell 7(2), 129-141 (2005).
67. Jorgensen HG, Allan Ek, Jordanides NE, Mountford JC, Holyoake TL. Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 109(9), 4016-4019 (2007).
68. Kantarjian HM, Hochhaus A, Saglio G et al. Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the Phase 3 randomised ENESTnd trial. Lancet Oncol. 12(9), 841-851 (2011).
69. Wei G, Rafiyath S, Liu D. First-line treatment for chronic myeloid leukemia: Dasatinib, nilotinib, or imatinib. J. Hematol. Oncol. 3, 47 (2010).
70. Soverini S, Hochhaus A, Nicolini FE et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: Recommendations from an expert panel on behalf of European LeukemiaNet. Blood 118(5), 1208-1215 (2011).
71. 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 16(5), 401-412 (2009).
72. Eiring AM, Khorashad JS, Morley K, Deininger MW. Advances in the treatment of chronic myeloid leukemia. BMC Med. 9, 99 (2011).
73. Cortes JE, Kantarjian HM, Brummendorf TH et al. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib. Blood 118(17), 4567-4576 (2011).
74. Kantarjian H, Le Coutre P, Cortes J et al. Phase I study of INNO-406, a dual Abl/Lyn kinase inhibitor, in Philadelphia chromosome-positive leukemias after imatinib resistance or intolerance. Cancer 116(11), 2665-2672 (2010).
75. Kelly KR, Ecsedy J, Medina E et al. The novel Aurora A kinase inhibitor MLN8237 is active in resistant chronic myeloid leukaemia and significantly increases the efficacy of nilotinib. J. Cell Mol. Med. 15(10), 2057-2070 (2011).
76. Bixby D, Talpaz M. Mechanisms of resistance to tyrosine kinase inhibitors in chronic myeloid leukemia and recent therapeutic strategies to overcome resistance. Hematology Am. Soc. Hematol. Educ. Program 461-476 (2009).
77. Shiotsu Y, Kiyoi H, Ishikawa Y et al. KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation. Blood 114(8), 1607-1617 (2009).
78. Zhang J, Adrian FJ, Jahnke W et al. Targeting BCR-ABL by combining allosteric with ATP-binding-site inhibitors. Nature 463(7280), 501-506 (2010).
79. Grebien F, Hantschel O, Wojcik J et al. Targeting the SH2-kinase interface in BCR-ABL inhibits leukemogenesis. Cell 147(2), 306-319 (2011).
80. Chan WW, Wise SC, Kaufman MD et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell 19(4), 556-568 (2011).
81. Nicolini FE, Chomel JC, Roy L et al. The durable clearance of the T315I BCR-ABL mutated clone in chronic phase chronic myelogenous leukemia patients on omacetaxine allows tyrosine kinase inhibitor rechallenge. Clin. Lymphoma Myeloma Leuk. 10(5), 394-399 (2010).
82. Allan EK, Holyoake TL, Craig AR, Jorgensen HG. Omacetaxine may have a role in chronic myeloid leukaemia eradication through downregulation of Mcl-1 and induction of apoptosis in stem/progenitor cells. Leukemia 25(6), 985-994 (2011).
83. Mohi MG, Boulton C, Gu TL et al. Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc. Natl Acad. Sci. USA 101(9), 3130-3135 (2004).
84. Sillaber C, Mayerhofer M, Bohm A et al. Evaluation of antileukaemic effects of rapamycin in patients with imatinib-resistant chronic myeloid leukaemia. Eur. J. Clin. Invest. 38(1), 43-52 (2008).
85. Mancini M, Petta S, Martinelli G, Barbieri E, Santucci MA. RAD 001 (everolimus) prevents mTOR and Akt late re-activation in response to imatinib in chronic myeloid leukemia. J. Cell. Biochem. 109(2), 320-328 (2010).
86. Carayol N, Vakana E, Sassano A et al. Critical roles for mTORC2- and rapamycin-insensitive mTORC1-complexes in growth and survival of BCR-ABL-expressing leukemic cells. Proc. Natl Acad. Sci. USA 107(28), 12469-12474 (2010).
87. Kharas MG, Janes MR, Scarfone VM et al. Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells. J. Clin. Invest. 118(9), 3038-3050 (2008).
88. Bellodi C, Lidonnici MR, Hamilton A et al. Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells. J. Clin. Invest. 119(5), 1109-1123 (2009).
89. Preudhomme C, Guilhot J, Nicolini FE et al. Imatinib plus peginterferon alfa-2a in chronic myeloid leukemia. N. Engl. J. Med. 363(26), 2511-2521 (2010).
90. Chen Y, Hu Y, Zhang H, Peng C, Li S. Loss of the Alox5 gene impairs leukemia stem cells and prevents chronic myeloid leukemia. Nat. Genet. 41(7), 783-792 (2009).
91. Rojas JM, Knight K, Watmough S et al. BCR-ABL peptide vaccination in healthy subjects: Immunological responses are equivalent to those in chronic myeloid leukaemia patients. Leuk. Res. 35(3), 369-372 (2011).
92. Jain N, Reuben JM, Kantarjian H et al. Synthetic tumor-specific breakpoint peptide vaccine in patients with chronic myeloid leukemia and minimal residual disease: A Phase 2 trial. Cancer 115(17), 3924-3934 (2009).
93. Bocchia M, Defina M, Aprile L et al. Complete molecular response in CML after p210 BCR-ABL1-derived peptide vaccination. Nat. Rev. Clin. Oncol. 7(10), 600-603 (2010).
94. Smahel M. Antigens in chronic myeloid leukemia: Implications for vaccine development. Cancer Immunol. Immunother. 60(12), 1655-1668 (2011).
95. An WG, Schulte TW, Neckers LM. The heat shock protein 90 antagonist geldanamycin alters chaperone association with p210BCR-ABL and v-src proteins before their degradation by the proteasome. Cell Growth Differ. 11(7), 355-360 (2000).
96. Wang Y, Trepel JB, Neckers LM, Giaccone G. STA-9090, a small-molecule Hsp90 inhibitor for the potential treatment of cancer. Curr. Opin. Investig. Drugs 11(12), 1466-1476 (2010).