Chronic Myeloid Leukemia: Advances in Understanding Disease Biology and Mechanisms of Resistance to Tyrosine Kinase Inhibitors

Current Hematologic Malignancy Reports

Volumn 10, Issue 2, 2015, Pages 158-166

  Eide, Christopher A ^a,b   O’Hare, Thomas ^c,d,e  

^a OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

^b HOWARD HUGHES MEDICAL INSTITUTE   (United States)

^c UNIVERSITY OF UTAH   (United States)

^d UNIVERSITY OF UTAH   (United States)

^e NONE   (United States)

Author keywords

BCR ABL1 compound mutation; BCR ABL1 independent resistance; Chronic myeloid leukemia (CML); Imatinib; Treatment free remission (TFR); Tyrosine kinase inhibitor (TKI)

Indexed keywords

BCR ABL PROTEIN; PROTEIN TYROSINE KINASE; PROTEIN TYROSINE KINASE INHIBITOR; ANTINEOPLASTIC AGENT; PROTEIN KINASE INHIBITOR;

CANCER CHEMOTHERAPY; CANCER REGRESSION; CANCER RESISTANCE; CHRONIC MYELOID LEUKEMIA; CLINICAL FEATURE; DRUG TREATMENT FAILURE; ENZYME ACTIVITY; ENZYME INHIBITION; GENE MUTATION; HUMAN; MAINTENANCE CHEMOTHERAPY; MULTICENTER STUDY (TOPIC); PHASE 1 CLINICAL TRIAL (TOPIC); PHILADELPHIA CHROMOSOME POSITIVE CELL; REVIEW; TREATMENT OUTCOME; TREATMENT RESPONSE; ANTAGONISTS AND INHIBITORS; CHEMISTRY; DRUG EFFECTS; DRUG RESISTANCE; ENZYMOLOGY; GENETICS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; METABOLISM; MOLECULARLY TARGETED THERAPY; MUTATION;

ANTINEOPLASTIC AGENTS; DRUG RESISTANCE, NEOPLASM; FUSION PROTEINS, BCR-ABL; HUMANS; LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE; MOLECULAR TARGETED THERAPY; MUTATION; PROTEIN KINASE INHIBITORS; PROTEIN-TYROSINE KINASES;

EID: 84929950286     PISSN: 15588211     EISSN: 1558822X     Source Type: Journal    
DOI: 10.1007/s11899-015-0248-3     Document Type: Review

References (67)

1. Eiring AM, Deininger MW. Individualizing kinase-targeted cancer therapy: the paradigm of chronic myeloid leukemia. Genome Biol. 2014;15(9):461.
2. O'Hare T, Zabriskie MS, Eiring AM, Deininger MW. Pushing the limits of targeted therapy in chronic myeloid leukaemia. Nat Rev Cancer. 2012;12(8):513–26.
3. Hughes TP, Saglio G, Kantarjian HM, Guilhot F, Niederwieser D, Rosti G, et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood. 2014;123(9):1353–60.
4. Jabbour E, Kantarjian HM, Saglio G, Steegmann JL, Shah NP, Boque C, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123(4):494–500.
5. Brummendorf TH, Cortes JE, de Souza CA, Guilhot F, Duvillie L, Pavlov D, et al. Bosutinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukaemia: results from the 24-month follow-up of the BELA trial. Br J Haematol. 2014. doi:10.1111/bjh.13108.
6. Gambacorti-Passerini C, Cortes JE, Lipton JH, Dmoszynska A, Wong RS, Rossiev V, et al. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia. Am J Hematol. 2014;89(10):947–53.
7. Kantarjian HM, Cortes JE, Kim DW, Khoury HJ, Brummendorf TH, Porkka K, et al. Bosutinib safety and management of toxicity in leukemia patients with resistance or intolerance to imatinib and other tyrosine kinase inhibitors. Blood. 2014;123(9):1309–18.
8. Cortes JE, Kim DW, Pinilla-Ibarz J, le Coutre P, Paquette R, Chuah C, et al. A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias. N Engl J Med. 2013;369(19):1783–96. These interim results (median follow-up: 15 months) for the multicenter PACE phase 2 trial of ponatinib in patients with CML or Ph+ ALL (initial dose: 45 mg once daily) find striking clinical benefit in heavily pre-treated CP-CML patients, irrespective of BCR-ABL1 mutation status at trial entry. Occurrences of arterial thrombosis and other severe vascular adverse events are noted, prompting dose adjustment and other proactive measures to optimize ponatinib treatment for patients lacking other therapeutic options.
9. Greuber EK, Smith-Pearson P, Wang J, Pendergast AM. Role of ABL family kinases in cancer: from leukaemia to solid tumours. Nat Rev Cancer. 2013;13(8):559–71.
10. Ren R. Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia. Nat Rev Cancer. 2005;5(3):172–83.
11. Deininger MW, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood. 2000;96(10):3343–56.
12. Li S, Ilaria Jr RL, Million RP, Daley GQ, Van Etten RA. The P190, P210, and P230 forms of the BCR/ABL oncogene induce a similar chronic myeloid leukemia-like syndrome in mice but have different lymphoid leukemogenic activity. J Exp Med. 1999;189(9):1399–412.
13. Apperley JF. Part I: mechanisms of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(11):1018–29.
14. Milojkovic D, Apperley J. Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res. 2009;15(24):7519–27.
15. O'Hare T, Shakespeare WC, Zhu X, Eide CA, Rivera VM, Wang F, 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(5):401–12.
16. Shah NP, Skaggs BJ, Branford S, Hughes TP, Nicoll JM, Paquette RL, et al. Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency. J Clin Invest. 2007;117(9):2562–9.
17. Khorashad JS, Kelley TW, Szankasi P, Mason CC, Soverini S, Adrian LT, et al. BCR-ABL1 compound mutations in tyrosine kinase inhibitor-resistant CML: frequency and clonal relationships. Blood. 2013;121(3):489–98.
18. Zabriskie MS, Eide CA, Tantravahi SK, Vellore NA, Estrada J, Nicolini FE, et al. BCR-ABL1 compound mutations combining key kinase domain positions confer clinical resistance to ponatinib in Ph chromosome-positive leukemia. Cancer Cell. 2014;26(3):428–42. This study investigates clinically observed compound mutations involving 12 key positions within the BCR-ABL1 kinase domain. Among patients harboring compound mutations at the end of ponatinib treatment, 15/16 cases involved two key positions. In vitro cell proliferation assays confirmed that the effectiveness of ponatinib was substantially decreased in T315I-inclusive compound mutations. In contrast, non-T315I compound mutations exhibited variable sensitivity to ponatinib and other TKIs, raising the possibility that early detection of low-level compound mutations could be combined with inhibitor sensitivity studies to select TKIs capable of suppressing resistant clones.
19. Soverini S, De Benedittis C, Machova Polakova K, Brouckova A, Horner D, Iacono M, et al. Unraveling the complexity of tyrosine kinase inhibitor-resistant populations by ultra-deep sequencing of the BCR-ABL kinase domain. Blood. 2013;122(9):1634–48.
20. Gibbons DL, Pricl S, Posocco P, Laurini E, Fermeglia M, Sun H, et al. Molecular dynamics reveal BCR-ABL1 polymutants as a unique mechanism of resistance to PAN-BCR-ABL1 kinase inhibitor therapy. Proc Natl Acad Sci U S A. 2014;111(9):3550–5.
21. Kastner R, Zopf A, Preuner S, Proll J, Niklas N, Foskett P, et al. Rapid identification of compound mutations in patients with Philadelphia-positive leukaemias by long-range next generation sequencing. Eur J Cancer. 2014;50(4):793–800.
22. Buffa P, Romano C, Pandini A, Massimino M, Tirro E, Di Raimondo F, et al. BCR-ABL residues interacting with ponatinib are critical to preserve the tumorigenic potential of the oncoprotein. FASEB J. 2014;28(3):1221–36.
23. Parker WT, Phillis SR, Yeung DT, Hughes TP, Scott HS, Branford S. Many BCR-ABL1 compound mutations reported in chronic myeloid leukemia patients may actually be artifacts due to PCR-mediated recombination. Blood. 2014;124(1):153–5.
24. Khateb M, Ruimi N, Khamisie H, Najajreh Y, Mian A, Metodieva A, et al. Overcoming Bcr-Abl T315I mutation by combination of GNF-2 and ATP competitors in an Abl-independent mechanism. BMC Cancer. 2012;12:563.
25. Gray NS, Fabbro D. Discovery of allosteric bcr-abl inhibitors from phenotypic screen to clinical candidate. Methods Enzymol. 2014;548:173–88.
26. Iacob RE, Zhang J, Gray NS, Engen JR. Allosteric interactions between the myristate- and ATP-site of the Abl kinase. PLoS One. 2011;6(1):e15929.
27. Zhang J, Adrian FJ, Jahnke W, Cowan-Jacob SW, Li AG, Iacob RE, et al. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature. 2010;463(7280):501–6.
28. Donato NJ, Wu JY, Stapley J, Gallick G, Lin H, Arlinghaus R, et al. BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571. Blood. 2003;101(2):690–8.
29. Gioia R, Leroy C, Drullion C, Lagarde V, Etienne G, Dulucq S, et al. Quantitative phosphoproteomics revealed interplay between Syk and Lyn in the resistance to nilotinib in chronic myeloid leukemia cells. Blood. 2011;118(8):2211–21.
30. Burchert A, Wang Y, Cai D, von Bubnoff N, Paschka P, Muller-Brusselbach S, et al. Compensatory PI3-kinase/Akt/mTor activation regulates imatinib resistance development. Leukemia. 2005;19(10):1774–82.
31. Agarwal A, Eide CA, Harlow A, Corbin AS, Mauro MJ, Druker BJ, et al. An activating KRAS mutation in imatinib-resistant chronic myeloid leukemia. Leukemia. 2008;22(12):2269–72.
32. Wang Y, Cai D, Brendel C, Barett C, Erben P, Manley PW, et al. Adaptive secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mediates imatinib and nilotinib resistance in BCR/ABL+ progenitors via JAK-2/STAT-5 pathway activation. Blood. 2007;109(5):2147–55.
33. Cortes JE, Kantarjian H, Shah NP, Bixby D, Mauro MJ, Flinn I, et al. Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012;367(22):2075–88.
34. Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, O'Hare T, et al. Wnt/Ca2+/NFAT signaling maintains survival of Ph + leukemia cells upon inhibition of Bcr-Abl. Cancer Cell. 2010;18(1):74–87.
35. Packer LM, Rana S, Hayward R, O'Hare T, Eide CA, Rebocho A, et al. Nilotinib and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug-resistant chronic myeloid leukemia. Cancer Cell. 2011;20:715–27.
36. Asmussen J, Lasater EA, Tajon C, Oses-Prieto J, Jun YW, Taylor BS, et al. MEK-dependent negative feedback underlies BCR-ABL-mediated oncogene addiction. Cancer Discov. 2014;4(2):200–15. Asmussen and colleagues use phosphoproteomics analysis on CML cells transiently exposed to dasatinib to show that BCR-ABL1 may rewire and suppress normal growth factor-dependent signaling. Gene expression analysis implicates a MEK-driven negative feedback circuit in this process, which remains intact upon TKI-mediated interruption of BCR-ABL1 signaling and enforces an irreversible apoptosis program in temporal advance of rescue by pro-survival growth factors.
37. Ma L, Shan Y, Bai R, Xue L, Eide CA, Ou J, et al. A therapeutically targetable mechanism of BCR-ABL-independent imatinib resistance in chronic myeloid leukemia. Sci Transl Med. 2014;6(252):252ra121. Ma and colleagues identify a panel of different genes whose silencing by RNAi results in imatinib resistance in CML cells, nearly uniformly leading to upregulation of PRKCH. This in turn drives persistent activation of RAF/MEK/ERK signaling after imatinib treatment, and these findings are validated in primary TKI-refractory CML specimens and using in vivo mouse models. The authors also report selective persistent RAF/MEK/ERK activity in CML stem vs. progenitor cells, a difference that may potentially be exploited with BCR-ABL1/MEK inhibitor combinations.
38. Eiring AM, Page BD, Kraft IL, Mason CC, Vellore NA, Resetca D, et al. Combined STAT3 and BCR-ABL1 inhibition induces synthetic lethality in therapy-resistant chronic myeloid leukemia. Leukemia. 2014. doi:10.1038/leu.2014.245.
39. Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J. Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell. 2014;26(2):207–21.
40. Traer E, Mackenzie R, Snead J, Agarwal A, Eiring AM, O'Hare T, et al. Blockade of JAK2-mediated extrinsic survival signals restores sensitivity of CML cells to ABL inhibitors. Leukemia. 2012;26:1140–3.
41. Bewry NN, Nair RR, Emmons MF, Boulware D, Pinilla-Ibarz J, Hazlehurst LA. Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther. 2008;7(10):3169–75.
42. Beer PA, Knapp DJ, Miller PH, Kannan N, Sloma I, Heel K, et al. Disruption of IKAROS activity in primitive chronic phase CML cells mimics myeloid disease progression. Blood. 2014 Nov 4.
43. Mullighan CG, Miller CB, Radtke I, Phillips LA, Dalton J, Ma J, et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. 2008;453(7191):110–4.
44. Mauro MJ, Druker BJ, Maziarz RT. Divergent clinical outcome in two CML patients who discontinued imatinib therapy after achieving a molecular remission. Leuk Res. 2004;28 Suppl 1:S71–3.
45. Kuwabara A, Babb A, Ibrahim A, Milojkovic D, Apperley J, Bua M, et al. Poor outcome after reintroduction of imatinib in patients with chronic myeloid leukemia who interrupt therapy on account of pregnancy without having achieved an optimal response. Blood. 2010;116(6):1014–6.
46. Kumari A, Brendel C, Hochhaus A, Neubauer A, Burchert A. Low BCR-ABL expression levels in hematopoietic precursor cells enable persistence of chronic myeloid leukemia under imatinib. Blood. 2012;119(2):530–9.
47. 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(1):396–409.
48. Hamilton A, Helgason GV, Schemionek M, Zhang B, Myssina S, Allan EK, et al. Chronic myeloid leukemia stem cells are not dependent on Bcr-Abl kinase activity for their survival. Blood. 2012;119(6):1501–10.
49. Ng KP, Manjeri A, Lee KL, Huang W, Tan SY, Chuah CT, et al. Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition. Blood. 2014;123(21):3316–26.
50. Chen Y, Peng C, Abraham SA, Shan Y, Guo Z, Desouza N, et al. Arachidonate 15-lipoxygenase is required for chronic myeloid leukemia stem cell survival. J Clin Invest. 2014;124(9):3847–62.
51. Kobayashi CI, Takubo K, Kobayashi H, Nakamura-Ishizu A, Honda H, Kataoka K, et al. The IL-2/CD25 axis maintains distinct subsets of chronic myeloid leukemia-initiating cells. Blood. 2014;123(16):2540–9.
52. Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D, et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-beta-catenin signaling. Blood. 2013;121(10):1824–38.
53. MacLean AL, Filippi S, Stumpf MP. The ecology in the hematopoietic stem cell niche determines the clinical outcome in chronic myeloid leukemia. Proc Natl Acad Sci U S A. 2014;111(10):3883–8.
54. Krause DS, Lazarides K, Lewis JB, von Andrian UH, Van Etten RA. Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche. Blood. 2014;123(9):1361–71. Investigation of adhesion pathways that contribute to engraftment of BCR-ABL1-driven, CML-like myeloproliferative neoplasia in a mouse retroviral transduction/transplantation model reveal that BCR-ABL1 LSCs are more dependent on selectin-mediated homing and engraftment than normal hematopoietic stem cells. These observations and earlier reports from the same group suggest that blockade of selectin-ligand interactions could mitigate leukemic engraftment and relapse in autografted patients.
55. Zhang J, Ren X, Shi W, Wang S, Chen H, Zhang B, et al. Small molecule Me6TREN mobilizes hematopoietic stem/progenitor cells by activating MMP-9 expression and disrupting SDF-1/CXCR4 axis. Blood. 2014;123(3):428–41.
56. Mahon FX, Etienne G. Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res. 2014;20(2):310–22.
57. Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, 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. 2010;11(11):1029–35.
58. Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, et al. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013;122(4):515–22.
59. Cross NC, White HE, Muller MC, Saglio G, Hochhaus A. Standardized definitions of molecular response in chronic myeloid leukemia. Leukemia. 2012;26(10):2172–5.
60. Shah NP, Guilhot F, Cortes JE, Schiffer CA, le Coutre P, Brummendorf TH, et al. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study. Blood. 2014;123(15):2317–24.
61. Hughes TP, Lipton JH, Spector N, Cervantes F, Pasquini R, Clementino NC, et al. Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib. Blood. 2014;124(5):729–36.
62. Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, et al. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014;32(5):424–30.
63. Shah NP, Talpaz M, Deininger MW, Mauro MJ, Flinn IW, Bixby D, et al. Ponatinib in patients with refractory acute myeloid leukaemia: findings from a phase 1 study. Br J Haematol. 2013;162(4):548–52.
64. Smith CC, Lasater EA, Zhu X, Lin KC, Stewart WK, Damon LE, et al. Activity of ponatinib against clinically-relevant AC220-resistant kinase domain mutants of FLT3-ITD. Blood. 2013;121(16):3165–71.
65. Smith CC, Wang Q, Chin CS, Salerno S, Damon LE, Levis MJ, et al. Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia. Nature. 2012;485(7397):260–3.
66. Wang WL, Conley A, Reynoso D, Nolden L, Lazar AJ, George S, et al. Mechanisms of resistance to imatinib and sunitinib in gastrointestinal stromal tumor. Cancer Chemother Pharmacol. 2011;67 Suppl 1:S15–24.
67. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer. 2011;11(12):865–78.