Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
International Journal of Hematology
Published in: International Journal of Hematology 5/2021

01-05-2021 | Chronic Myeloid Leukemia | Progress in Hematology

Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia

Authors: Hyewon Lee, Igor Novitzky Basso, Dennis Dong Hwan Kim

Published in: International Journal of Hematology | Issue 5/2021

Login to get access

Abstract

BCR-ABL1 plays a key role in the pathogenesis of chronic myeloid leukemia (CML), and it has been investigated as a druggable target of tyrosine kinase inhibitors (TKIs) over two decades. Since imatinib, the first TKI for anti-cancer therapy, was successfully applied in CML therapy, further generation TKIs and a novel allosteric inhibitor targeting the myristate binding site have been developed as alternative options for CML management. However, significant concerns regarding toxicity profiles, especially in long-term treatment, have emerged from TKI clinical data. Efforts to reduce adverse events and serious complications are warranted not only for survival, but also quality of life in CML patients. A better understanding of the mechanism of action will help to identify on- and off-target effects of TKIs, and guide personalized TKI drug selection in each individual CML patient. Herein, this review summarizes the biologic mechanism of BCR-ABL1 inhibition and differential target spectra, and related off-target effects of each TKI.
Literature
1.
Nowell PC, Hungerford DA. Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst. 1960;25:85–109.PubMed
2.
Groffen J, Stephenson JR, Heisterkamp N, Bartram C, de Klein A, Grosveld G. The human c-abl oncogene in the Philadelphia translocation. J Cell Physiol Suppl. 1984;3:179–91.PubMedCrossRef
3.
Rowley JD. Letter: a new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining. Nature. 1973;243:290–3.PubMedCrossRef
4.
Cohen MH, Williams G, Johnson JR, Duan J, Gobburu J, Rahman A, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002;8:935–42.PubMed
5.
O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994–1004.PubMedCrossRef
6.
Hochhaus A, Saglio G, Hughes TP, Larson RA, Kim DW, Issaragrisil S, et al. Long-term benefits and risks of front-line nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial. Leukemia. 2016;30:1044–54.PubMedPubMedCentralCrossRef
7.
Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J, Boque C, et al. Final 5-year study results of DASISION: the dasatinib versus imatinib study in treatment-naive chronic myeloid leukemia patients trial. J Clin Oncol. 2016;34:2333–40.PubMedPubMedCentralCrossRef
8.
Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ, Chuah C, Kim DW, et al. Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. J Clin Oncol. 2018;36:231–7.PubMedCrossRef
9.
Lipton JH, Chuah C, Guerci-Bresler A, Rosti G, Simpson D, Assouline S, et al. Ponatinib versus imatinib for newly diagnosed chronic myeloid leukaemia: an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17:612–21.PubMedCrossRef
10.
Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC, Andersson TM. Life expectancy of patients with chronic myeloid leukemia approaches the life expectancy of the general population. J Clin Oncol. 2016;34:2851–7.PubMedCrossRef
11.
Hughes TP, Ross DM. Moving treatment-free remission into mainstream clinical practice in CML. Blood. 2016;128:17–23.PubMedCrossRef
12.
Shah NP. Advanced CML: therapeutic options for patients in accelerated and blast phases. J Natl Compr Canc Netw. 2008;6(Suppl 2):S31–6.PubMed
13.
14.
Clark SS, McLaughlin J, Crist WM, Champlin R, Witte ON. Unique forms of the abl tyrosine kinase distinguish Ph1-positive CML from Ph1-positive ALL. Science. 1987;235:85–8.PubMedCrossRef
15.
Groffen J, Stephenson JR, Heisterkamp N, de Klein A, Bartram CR, Grosveld G. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell. 1984;36:93–9.PubMedCrossRef
16.
Hermans A, Heisterkamp N, von Linden M, van Baal S, Meijer D, van der Plas D, et al. Unique fusion of bcr and c-abl genes in Philadelphia chromosome positive acute lymphoblastic leukemia. Cell. 1987;51:33–40.PubMedCrossRef
17.
18.
19.
Soverini S, Mancini M, Bavaro L, Cavo M, Martinelli G. Chronic myeloid leukemia: the paradigm of targeting oncogenic tyrosine kinase signaling and counteracting resistance for successful cancer therapy. Mol Cancer. 2018;17:49.PubMedPubMedCentralCrossRef
20.
Melo JV, Deininger MW. Biology of chronic myelogenous leukemia—signaling pathways of initiation and transformation. Hematol Oncol Clin North Am. 2004;18:545–68 (vii–viii).PubMedCrossRef
21.
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.PubMedCrossRef
22.
Kelliher MA, McLaughlin J, Witte ON, Rosenberg N. Induction of a chronic myelogenous leukemia-like syndrome in mice with v-abl and BCR/ABL. Proc Natl Acad Sci USA. 1990;87:6649–53.PubMedCrossRefPubMedCentral
23.
Ramaraj P, Singh H, Niu N, Chu S, Holtz M, Yee JK, et al. 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;64:5322–31.PubMedCrossRef
24.
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.PubMedCrossRef
25.
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.PubMedPubMedCentralCrossRef
26.
Uitdehaag JC, de Roos JA, van Doornmalen AM, Prinsen MB, de Man J, Tanizawa Y, et al. Comparison of the cancer gene targeting and biochemical selectivities of all targeted kinase inhibitors approved for clinical use. PLoS ONE. 2014;9:e92146.PubMedPubMedCentralCrossRef
27.
Kitagawa D, Yokota K, Gouda M, Narumi Y, Ohmoto H, Nishiwaki E, et al. Activity-based kinase profiling of approved tyrosine kinase inhibitors. Genes Cells. 2013;18:110–22.PubMedCrossRef
28.
Hantschel O, Rix U, Superti-Furga G. Target spectrum of the BCR-ABL inhibitors imatinib, nilotinib and dasatinib. Leuk Lymphoma. 2008;49:615–9.PubMedCrossRef
29.
Giles FJ, O’Dwyer M, Swords R. Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia. Leukemia. 2009;23:1698–707.PubMedCrossRef
30.
Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S, Hughes TP, et al. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N Engl J Med. 2017;376:917–27.PubMedPubMedCentralCrossRef
31.
Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001;293:876–80.PubMedCrossRef
32.
Kwak JY, Kim SH, Oh SJ, Zang DY, Kim H, Kim JA, et al. Phase III clinical trial (RERISE study) results of efficacy and safety of radotinib compared with imatinib in newly diagnosed chronic phase chronic myeloid leukemia. Clin Cancer Res. 2017;23:7180–8.PubMedCrossRef
33.
McGary EC, Weber K, Mills L, Doucet M, Lewis V, Lev DC, et al. Inhibition of platelet-derived growth factor-mediated proliferation of osteosarcoma cells by the novel tyrosine kinase inhibitor STI571. Clin Cancer Res. 2002;8:3584–91.PubMed
34.
Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood. 2000;96:925–32.PubMedCrossRef
35.
Weisberg E, Manley P, Mestan J, Cowan-Jacob S, Ray A, Griffin JD. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. Br J Cancer. 2006;94:1765–9.PubMedPubMedCentralCrossRef
36.
Kantarjian HM, Hughes TP, Larson RA, Kim DW, Issaragrisil S, le Coutre P, et al. Long-term outcomes with front-line nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia. 2021;35:440–53.PubMedPubMedCentralCrossRef
37.
Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966–84.PubMedPubMedCentralCrossRef
38.
Tokarski JS, Newitt JA, Chang CY, Cheng JD, Wittekind M, Kiefer SE, et al. The structure of Dasatinib (BMS-354825) bound to activated ABL kinase domain elucidates its inhibitory activity against imatinib-resistant ABL mutants. Cancer Res. 2006;66:5790–7.PubMedCrossRef
39.
Shah NP, Tran C, Lee FY, Chen P, Norris D, Sawyers CL. Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 2004;305:399–401.PubMedCrossRef
40.
Golas JM, Arndt K, Etienne C, Lucas J, Nardin D, Gibbons J, et al. SKI-606, a 4-anilino-3-quinolinecarbonitrile dual inhibitor of Src and Abl kinases, is a potent antiproliferative agent against chronic myelogenous leukemia cells in culture and causes regression of K562 xenografts in nude mice. Cancer Res. 2003;63:375–81.PubMed
41.
Puttini M, Coluccia AM, Boschelli F, Cleris L, Marchesi E, Donella-Deana A, et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhibitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 2006;66:11314–22.PubMedCrossRef
42.
43.
Brümmendorf TH, Cortes JE, Milojkovic D, Gambacorti-Passerini C, Clark RE, le Coutre PE, et al. Bosutinib (BOS) versus imatinib for newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML): final 5-year results from the bfore tria. Blood. 2020;136:41–2.CrossRef
44.
Remsing Rix LL, Rix U, Colinge J, Hantschel O, Bennett KL, Stranzl T, et al. Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells. Leukemia. 2009;23:477–85.PubMedCrossRef
45.
Mancini M, Brusa G, Zuffa E, Corrado P, Martinelli G, Grafone T, et al. Persistent Cdk2 inactivation drives growth arrest of BCR-ABL-expressing cells in response to dual inhibitor of SRC and ABL kinases SKI606. Leuk Res. 2007;31:979–87.PubMedCrossRef
46.
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;367:2075–88.PubMedPubMedCentralCrossRef
47.
Cortes JE, Lomaia E, Turkina A, Moiraghi B, Sutton MU, Pavlovsky C, et al. Interim analysis (IA) of OPTIC: a dose-ranging study of three ponatinib (PON) starting doses. J Clin Oncol. 2020;38:7502.CrossRef
48.
Hughes TP, Mauro MJ, Cortes JE, Minami H, Rea D, DeAngelo DJ, et al. Asciminib in chronic myeloid leukemia after ABL kinase inhibitor failure. N Engl J Med. 2019;381:2315–26.PubMedPubMedCentralCrossRef
49.
Wylie AA, Schoepfer J, Jahnke W, Cowan-Jacob SW, Loo A, Furet P, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature. 2017;543:733–7.PubMedCrossRef
50.
Manley PW, Barys L, Cowan-Jacob SW. The specificity of asciminib, a potential treatment for chronic myeloid leukemia, as a myristate-pocket binding ABL inhibitor and analysis of its interactions with mutant forms of BCR-ABL1 kinase. Leuk Res. 2020;98:106458.PubMedCrossRef
51.
Lindström HJG, Friedman R. The effects of combination treatments on drug resistance in chronic myeloid leukaemia: an evaluation of the tyrosine kinase inhibitors axitinib and asciminib. BMC Cancer. 2020;20:397.CrossRef
52.
Eide CA, Zabriskie MS, Savage Stevens SL, Antelope O, Vellore NA, Than H, et al. Combining the allosteric inhibitor asciminib with ponatinib suppresses emergence of and restores efficacy against highly resistant BCR-ABL1 mutants. Cancer Cell. 2019;36(431–43):e5.
53.
Hochhaus A, Boquimpani C, Rea D, Minami Y, Lomaia E, Voloshin S, et al. Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib (BOS) in patients (Pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). Blood. 2020;136(Suppl 2):LBA-4.CrossRef
54.
Kerkela R, Grazette L, Yacobi R, Iliescu C, Patten R, Beahm C, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12:908–16.PubMedCrossRef
55.
Ostman A, Heldin CH. PDGF receptors as targets in tumor treatment. Adv Cancer Res. 2007;97:247–74.PubMedCrossRef
56.
Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287–95.PubMedPubMedCentralCrossRef
57.
Lombardo LJ, Lee FY, Chen P, Norris D, Barrish JC, Behnia K, et al. Discovery of N-(2-chloro-6-methyl- phenyl)-2-(6-(4-(2-hydroxyethyl)-piperazin-1-yl)-2-methylpyrimidin-4-ylamino)thiazole-5-carbox-amide (BMS-354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 2004;47:6658–61.PubMedCrossRef
58.
Schlessinger J. New roles for Src kinases in control of cell survival and angiogenesis. Cell. 2000;100:293–6.PubMedCrossRef
59.
Quintas-Cardama A, Kantarjian H, O’Brien S, Borthakur G, Bruzzi J, Munden R, et al. Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure. J Clin Oncol. 2007;25:3908–14.PubMedCrossRef
60.
61.
Alvarez-Aznar A, Muhl L, Gaengel K. VEGF receptor tyrosine kinases: key regulators of vascular function. Curr Top Dev Biol. 2017;123:433–82.PubMedCrossRef
62.
Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res. 1993;60:1–41.PubMed
63.
Wesche J, Haglund K, Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. 2011;437:199–213.PubMedCrossRef
64.
Quek LS, Pasquet JM, Hers I, Cornall R, Knight G, Barnes M, et al. Fyn and Lyn phosphorylate the Fc receptor gamma chain downstream of glycoprotein VI in murine platelets, and Lyn regulates a novel feedback pathway. Blood. 2000;96:4246–53.PubMedCrossRef
65.
Milam KE, Parikh SM. The angiopoietin-Tie2 signaling axis in the vascular leakage of systemic inflammation. Tissue Barriers. 2015;3:e957508.PubMedCrossRef
66.
Cirmi S, El Abd A, Letinier L, Navarra M, Salvo F. Cardiovascular toxicity of tyrosine kinase inhibitors used in chronic myeloid leukemia: an analysis of the FDA adverse event reporting system database (FAERS). Cancers (Basel). 2020;12:826.CrossRef
67.
Jain P, Kantarjian H, Boddu PC, Nogueras-Gonzalez GM, Verstovsek S, Garcia-Manero G, et al. Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after front-line TKIs. Blood Adv. 2019;3:851–61.PubMedPubMedCentralCrossRef
68.
Vandyke K, Fitter S, Drew J, Fukumoto S, Schultz CG, Sims NA, et al. Prospective histomorphometric and DXA evaluation of bone remodeling in imatinib-treated CML patients: evidence for site-specific skeletal effects. J Clin Endocrinol Metab. 2013;98:67–76.PubMedCrossRef
69.
Aleman JO, Farooki A, Girotra M. Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies. Endocr Relat Cancer. 2014;21:R247–59.PubMedCrossRef
70.
Ratajczak MZ, Luger SM, DeRiel K, Abrahm J, Calabretta B, Gewirtz AM. Role of the KIT protooncogene in normal and malignant human hematopoiesis. Proc Natl Acad Sci USA. 1992;89:1710–4.PubMedCrossRefPubMedCentral
71.
Redaelli S, Mologni L, Rostagno R, Piazza R, Magistroni V, Ceccon M, et al. Three novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors. Am J Hematol. 2012;87:E125–8.PubMedCrossRef
Metadata
Title
Target spectrum of the BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia
Authors
Hyewon Lee
Igor Novitzky Basso
Dennis Dong Hwan Kim
Publication date
01-05-2021
Publisher
Springer Singapore
Published in
International Journal of Hematology / Issue 5/2021
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-021-03126-6

Other articles of this Issue 5/2021

International Journal of Hematology 5/2021 Go to the issue

Original Article

WT1-specific CD8 + cytotoxic T cells with the capacity for antigen-specific expansion accumulate in the bone marrow in MDS

Case Report

First reported case of congenital thrombotic thrombocytopenic purpura in Taiwan with novel mutation of ADAMTS13 gene

Original Article

Characteristics and transplant outcome of myeloid sarcoma: a single-institute study

Original Article

Risk factors for delayed elimination of high-dose methotrexate in childhood acute lymphoblastic leukemia and lymphoma

Progress in Hematology

Evolution of CML treatment

Rapid Communication

MPL exon 10 mutations other than canonical MPL W515L/K mutations identified by in-house MPL exon 10 direct sequencing in essential thrombocythemia
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits