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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

A Chemical Approach to Overcome Tyrosine Kinase Inhibitors Resistance: Learning from Chronic Myeloid Leukemia

Author(s): Enrico Zanforlin, Giuseppe Zagotto* and Giovanni Ribaudo

Volume 26, Issue 33, 2019

Page: [6033 - 6052] Pages: 20

DOI: 10.2174/0929867325666180607092451

Price: $65


Background: The possibilities of treatment for oncological diseases are growing enormously in the last decades. Unfortunately, these developments have led to the onset of resistances with regards to the new treatments. This is particularly true if we face with the therapeutic field of Tyrosine Kinase Inhibitors (TKIs). This review gives an overview of possible TKI resistances that can occur during the treatment of an oncologic diesease and available strategies that can be adopted, taking cues from a successful example such as CML.

Methods: We performed a literature search for peer-reviewed articles using different databases, such as PubMed and Scopus, and exploiting different keywords and different logical operators.

Results: 68 papers were included in the review. Twenty-four papers give an overview of the causes of TKIs resistances in the wide oncologic field. The remaining papers deal CML, deeply analysing the TKIs Resistances present in this pathology and the strategies adopted to overcome them.

Conclusion: The aim of this review is to furnish an overview and a methodological guideline for the approach and the overcoming of TKIs Resistances.

Keywords: Cancer, TKI, chronic myeloid leukemia, resistance, Bcr-Abl, imatinib, kinase, asciminib.

Paul, M.K.; Mukhopadhyay, A.K. Tyrosine kinase - Role and significance in Cancer. Int. J. Med. Sci., 2004, 1(2), 101-115.
[] [PMID: 15912202]
Bononi, A.; Agnoletto, C.; De Marchi, E.; Marchi, S.; Patergnani, S.; Bonora, M.; Giorgi, C.; Missiroli, S.; Poletti, F.; Rimessi, A.; Pinton, P. Protein kinases and phosphatases in the control of cell fate. Enzyme Res., 2011.2011329098
[] [PMID: 21904669]
Cross, T.G.; Scheel-Toellner, D.; Henriquez, N.V.; Deacon, E.; Salmon, M.; Lord, J.M. Serine/threonine protein kinases and apoptosis. Exp. Cell Res., 2000, 256(1), 34-41.
[] [PMID: 10739649]
Knight, Z.A.; Lin, H.; Shokat, K.M. Targeting the cancer kinome through polypharmacology. Nat. Rev. Cancer, 2010, 10(2), 130-137.
[] [PMID: 20094047]
Gross, S.; Rahal, R.; Stransky, N.; Lengauer, C.; Hoeflich, K.P. Targeting cancer with kinase inhibitors. J. Clin. Invest., 2015, 125(5), 1780-1789.
[] [PMID: 25932675]
Shi, Y. Serine/threonine phosphatases: mechanism through structure. Cell, 2009, 139(3), 468-484.
[] [PMID: 19879837]
Malhotra, V.; Perry, M.C. Classical chemotherapy: mechanisms, toxicities and the therapeutic window. Cancer Biol. Ther., 2003, 2(4), 2-4.
[PMID: 14508075]
Padma, V.V. An overview of targeted cancer therapy. Biomedicine (Taipei), 2015, 5(4), 19.
[] [PMID: 26613930]
TIME Magazine U.S. Edition, May 28 2001, Vol. 157.
Fabbro, D.; Cowan-Jacob, S.W.; Moebitz, H. Ten things you should know about protein kinases: IUPHAR Review 14. Br. J. Pharmacol., 2015, 172(11), 2675-2700.
[] [PMID: 25630872]
Camidge, D.R.; Pao, W.; Sequist, L.V. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat. Rev. Clin. Oncol., 2014, 11(8), 473-481.
[] [PMID: 24981256]
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), 2009, 461-476.
[] [PMID: 20008232]
Rexer, B.N.; Engelman, J.A.; Arteaga, C.L. Overcoming resistance to tyrosine kinase inhibitors: lessons learned from cancer cells treated with EGFR antagonists. Cell Cycle, 2009, 8(1), 18-22.
[] [PMID: 19106609]
Chen, Y.; Fu, L. Mechanisms of acquired resistance to tyrosine kinase inhibitors. Acta Pharm. Sin. B, 2011, 1(4), 197-207.
Rosenzweig, S.A. Acquired resistance to drugs targeting receptor tyrosine kinases. Biochem. Pharmacol., 2012, 83(8), 1041-1048.
[] [PMID: 22227013]
Eide, C.A.; O’Hare, T. Chronic myeloid leukemia: advances in understanding disease biology and mechanisms of resistance to tyrosine kinase inhibitors. Curr. Hematol. Malig. Rep., 2015, 10(2), 158-166.
[] [PMID: 25700679]
Than, H.; Chuah, C.; Ong, S.T. Molecular mechanism of TKI resistance and potential approaches to overcome resistance; Molecular Pathogenesis and Treatment of Chronic Myelogenous Leukemia, 2016, pp. 167-182.
Nakada, M.; Kita, D.; Watanabe, T.; Hayashi, Y.; Hamada, J. Mechanism of chemoresistance against tyrosine kinase inhibitors in malignant glioma. Brain Tumor Pathol., 2014, 31(3), 198-207.
[] [PMID: 24399202]
Gainor, J.F.; Shaw, A.T. Emerging paradigms in the development of resistance to tyrosine kinase inhibitors in lung cancer. J. Clin. Oncol., 2013, 31(31), 3987-3996.
[] [PMID: 24101047]
Ahsan, A. Lung Cancer and Personalized Medicine, 2016, 893, 137-153.
Huang, L.; Fu, L. Mechanisms of resistance to EGFR tyrosine kinase inhibitors. Acta Pharm. Sin. B, 2015, 5(5), 390-401.
[] [PMID: 26579470]
Tabarestani, S.; Movafagh, A. New developments in chronic myeloid leukemia: implications for therapy. Iran. J. Cancer Prev., 2016, 9(1)e3961
[] [PMID: 27366312]
Holyoake, T.L.; Vetrie, D. The chronic myeloid leukemia stem cell: stemming the tide of persistence. Blood, 2017, 129(12), 1595-1606.
[ 10.1182/blood-2016-09-696013] [PMID: 28159740]
Neviani, P.; Harb, J.G.; Oaks, J.J.; Santhanam, R.; Walker, C.J.; Ellis, J.J.; Ferenchak, G.; Dorrance, A.M.; Paisie, C.A.; Eiring, A.M.; Ma, Y.; Mao, H.C.; Zhang, B.; Wunderlich, M.; May, P.C.; Sun, C.; Saddoughi, S.A.; Bielawski, J.; Blum, W.; Klisovic, R.B.; Solt, J.A.; Byrd, J.C.; Volinia, S.; Cortes, J.; Huettner, C.S.; Koschmieder, S.; Holyoake, T.L.; Devine, S.; Caligiuri, M.A.; Croce, C.M.; Garzon, R.; Ogretmen, B.; Arlinghaus, R.B.; Chen, C.S.; Bittman, R.; Hokland, P.; Roy, D.C.; Milojkovic, D.; Apperley, J.; Goldman, J.M.; Reid, A.; Mulloy, J.C.; Bhatia, R.; Marcucci, G.; Perrotti, D. PP2A-activating drugs selectively eradicate TKI-resistant chronic myeloid leukemic stem cells. J. Clin. Invest., 2013, 123(10), 4144-4157.
[] [PMID: 23999433]
American Cancer Society. Available at: date: 5 January,. 2018.
An, X.; Tiwari, A.K.; Sun, Y.; Ding, P.R.; Ashby, C.R., Jr; Chen, Z.S. BCR-ABL tyrosine kinase inhibitors in the treatment of Philadelphia chromosome positive chronic myeloid leukemia: a review. Leuk. Res., 2010, 34(10), 1255-1268.
[] [PMID: 20537386]
Deininger, M.W.N.; Goldman, J.M.; Melo, J.V. The molecular biology of chronic myeloid leukemia. Blood, 2000, 96(10), 3343-3556.
[PMID: 11071626]
Lambert, G.K.; Duhme-Klair, A.K.; Morgan, T.; Ramjee, M.K. The background, discovery and clinical development of BCR-ABL inhibitors. Drug Discov. Today, 2013, 18(19-20), 992-1000.
[] [PMID: 23769978]
Panjarian, S.; Iacob, R.E.; Chen, S.; Engen, J.R.; Smithgall, T.E. Structure and dynamic regulation of Abl kinases. J. Biol. Chem., 2013, 288(8), 5443-5450.
[] [PMID: 23316053]
Zhao, X.; Ghaffari, S.; Lodish, H.; Malashkevich, V.N.; Kim, P.S. Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat. Struct. Biol., 2002, 9(2), 117-120.
[ 10.1038/nsb747] [PMID: 11780146]
Colicelli, J. ABL tyrosine kinases: evolution of function, regulation, and specificity. Sci. Signal., 2010, 3(139), re6.
[] [PMID: 20841568]
Kantarjian, H.M.; Talpaz, M.; Giles, F.; O’Brien, S.; Cortes, J. New insights into the pathophysiology of chronic myeloid leukemia and imatinib resistance. Ann. Intern. Med., 2006, 145(12), 913-923.
[] [PMID: 17179059]
Hantschel, O.; Superti-Furga, G. Regulation of the c-Abl and Bcr-Abl tyrosine kinases. Nat. Rev. Mol. Cell Biol., 2004, 5(1), 33-44.
[] [PMID: 14708008]
Fallacara, A.L.; Tintori, C.; Radi, M.; Schenone, S.; Botta, M. Insight into the allosteric inhibition of Abl kinase. J. Chem. Inf. Model., 2014, 54(5), 1325-1338.
[] [PMID: 24787133]
Lamontanara, A.J.; Gencer, E.B.; Kuzyk, O.; Hantschel, O. Mechanisms of resistance to BCR-ABL and other kinase inhibitors. Biochim. Biophys. Acta, 2013, 1834(7), 1449-1459.
[] [PMID: 23277196]
Miller, G.D.; Bruno, B.J.; Lim, C.S. Resistant mutations in CML and Ph + ALL – role of ponatinib. Biologics, 2014, 8, 243-254.
[] [PMID: 25349473]
Asaki, T.; Sugiyama, Y.; Hamamoto, T.; Higashioka, M.
Umehara, M.; Naito, H.; Niwa, T. Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase in-hibitors. Bioorg. Med. Chem. Lett., 2006, 16(5), 1421-1425.
[] [PMID: 16332440]
Cowan-Jacob, S.W.; Fendrich, G.; Floersheimer, A.; Furet, P.; Liebetanz, J.; Rummel, G.; Rheinberger, P.; Centeleghe, M.; Fabbro, D.; Manley, P.W. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia. Acta Crystallogr. D Biol. Crystallogr., 2007, 63(Pt 1), 80-93.
[] [PMID: 17164530]
Manley, P.W.; Stiefl, N.; Cowan-Jacob, S.W.; Kaufman, S.; Mestan, J.; Wartmann, M.; Wiesmann, M.; Woodman, R.; Gallagher, N. Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib. Bioorg. Med. Chem., 2010, 18(19), 6977-6986.
[] [PMID: 20817538]
Manley, P.W.; Cowan-Jacob, S.W.; Buchdunger, E.; Fabbro, D.; Fendrich, G.; Furet, P.; Meyer, T.; Zimmermann, J. Imatinib: a selective tyrosine kinase inhibitor. Eur. J. Cancer, 2002, 38(Suppl. 5), S19-S27.
[] [PMID: 12528769]
Li, J.J. Top Drugs I; Oxford University Press: New York, 2015.
Hantschel, O. Allosteric BCR-ABL inhibitors in Philadelphia chromosome-positive acute lymphoblastic leukemia: novel opportunities for drug combinations to overcome resistance. Haematologica, 2012, 97(2), 157-159.
[] [PMID: 22298820]
Olivieri, A.; Manzione, L. Dasatinib: a new step in molecular target therapy. Ann. Oncol., 2007, 18(Suppl. 6), vi42-vi46.
[] [PMID: 17591830]
Lucas, C.M.; Harris, R.J.; Holcroft, A.K.; Scott, L.J.; Carmell, N.; McDonald, E.; Polydoros, F.; Clark, R.E. Second generation tyrosine kinase inhibitors prevent disease progression in high-risk (high CIP2A) chronic myeloid leukaemia patients. Leukemia, 2015, 29(7), 1514-1523.
[] [PMID: 25765543]
Jabbour, E.; Kantarjian, H.; Cortes, J. Use of second- and third-generation tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia: an evolving treatment paradigm. Clin. Lymphoma Myeloma Leuk., 2015, 15(6), 323-334.
[] [PMID: 25971713]
Zhou, T.; Commodore, L.; Huang, W.S.; Wang, Y.; Thomas, M.; Keats, J.; Xu, Q.; Rivera, V.M.; Shakespeare, W.C.; Clackson, T.; Dalgarno, D.C.; Zhu, X. Structural mechanism of the Pan-BCR-ABL inhibitor ponatinib (AP24534): lessons for overcoming kinase inhibitor resistance. Chem. Biol. Drug Des., 2011, 77(1), 1-11.
[] [PMID: 21118377]
Nicolini, F.E.; Basak, G.W.; Kim, D.W.; Olavarria, E.; Pinilla-Ibarz, J.; Apperley, J.F.; Hughes, T.; Niederwieser, D.; Mauro, M.J.; Chuah, C.; Hochhaus, A.; Martinelli, G.; DerSarkissian, M.; Duh, M.S.; McGarry, L.J.; Kantarjian, H.M.; Cortes, J.E. Overall survival with ponatinib versus allogeneic stem cell transplantation in Philadelphia chromosome-positive leukemias with the T315I mutation. Cancer, 2017, 123(15), 2875-2880.
[] [PMID: 28387926]
Levinson, N.M.; Boxer, S.G. Structural and spectroscopic analysis of the kinase inhibitor bosutinib and an isomer of bosutinib binding to the Abl tyrosine kinase domain. PLoS One, 2012, 7(4)e29828
[] [PMID: 22493660]
Weisberg, E.; Manley, P.W.; Breitenstein, W.; Brüggen, J.; Cowan-Jacob, S.W.; Ray, A.; Huntly, B.; Fabbro, D.; Fendrich, G.; Hall-Meyers, E.; Kung, A.L.; Mestan, J.; Daley, G.Q.; Callahan, L.; Catley, L.; Cavazza, C.; Azam, M.; Neuberg, D.; Wright, R.D.; Gilliland, D.G.; Griffin, J.D. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell, 2005, 7(2), 129-141.
[] [PMID: 15710326]
Manley, P.W.; Stiefl, N.J. Progress in the Discovery of BCR-ABL Kinase Inhibitors for the Treatment of Leukemia. In: Cancer II. Topics in Medicinal Chemistry; Waring, M.J. (eds), , Ed.; Springer: Cham, 2017; Vol. 28, pp. 1-37.
Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.; Moquin, R.V.; Shen, Z.; Cook, L.S.; Doweyko, A.M.; Pitt, S.; Pang, S.; Shen, D.R.; Fang, Q.; de Fex, H.F.; McIntyre, K.W.; Shuster, D.J.; Gillooly, K.M.; Behnia, K.; Schieven, G.L.; Wityak, J.; Barrish, J.C. 2-aminothiazole as a novel kinase inhibitor template. Structure-activity relationship studies toward the discovery of N-(2-chloro-6-methylphenyl)-2-[[6-[4-(2-hydroxyethyl)-1- piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase inhibitor. J. Med. Chem., 2006, 49(23), 6819-6832.
[] [PMID: 17154512]
Tokarski, J.S.; Newitt, J.A.; Chang, C.Y.J.; Cheng, J.D.; Wittekind, M.; Kiefer, S.E.; Kish, K.; Lee, F.Y.F.; Borzillerri, R.; Lombardo, L.J.; Xie, D.; Zhang, Y.; Klei, H.E. 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(11), 5790-5797.
[] [PMID: 16740718]
Lindauer, M.; Hochhaus, A. Dasatinib. In: Small molecules in oncology. recent results in cancer research; Martens U. (eds), Springer, Berlin, Heidelberg,. , 2014; Vol. 201, pp. 27-65.
Blay, J.Y.; von Mehren, M. Nilotinib: a novel, selective tyrosine kinase inhibitor. Semin. Oncol., 2011, 38(1)(Suppl. 1), S3-S9.
[] [PMID: 21419934]
Jabbour, E.; Cortes, J.; Kantarjian, H. Nilotinib for the treatment of chronic myeloid leukemia: An evidence-based review. Core Evid., 2010, 4, 207-213.
[PMID: 20694077]
Kantarjian, H.M.; Hochhaus, A.; Saglio, G.; De Souza, C.; Flinn, I.W.; Stenke, L.; Goh, Y.T.; Rosti, G.; Nakamae, H.; Gallagher, N.J.; Hoenekopp, A.; Blakesley, R.E.; Larson, R.A.; Hughes, T.P. 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., 2011, 12(9), 841-851.
[] [PMID: 21856226]
Shukla, S.; Kouanda, A.; Silverton, L.; Talele, T.T.; Ambudkar, S.V. Pharmacophore modeling of nilotinib as an inhibitor of ATP-binding cassette drug transporters and BCR-ABL kinase using a three-dimensional quantitative structure-activity relationship approach. Mol. Pharm., 2014, 11(7), 2313-2322.
[] [PMID: 24865254]
Martinelli, G.; Iacobucci, I.; Soverini, S.; Palandri, F.; Castagnetti, F.; Rosti, G.; Baccarani, M. Nilotinib: a novel encouraging therapeutic option for chronic myeloid leukemia patients with imatinib resistance or intolerance. Biologics, 2007, 1(2), 121-127.
[PMID: 19707322]
Huang, W.S.; Metcalf, C.A.; Sundaramoorthi, R.; Wang, Y.; Zou, D.; Thomas, R.M.; Zhu, X.; Cai, L.; Wen, D.; Liu, S.; Romero, J.; Qi, J.; Chen, I.; Banda, G.; Lentini, S.P.; Das, S.; Xu, Q.; Keats, J.; Wang, F.; Wardwell, S.; Ning, Y.; Snodgrass, J.T.; Broudy, M.I.; Russian, K.; Zhou, T.; Commodore, L.; Narasimhan, N.I.; Mohemmad, Q.K.; Iuliucci, J.; Rivera, V.M.; Dalgarno, D.C.; Sawyer, T.K.; Clackson, T.; Shakespeare, W.C. Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenylbenzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J. Med. Chem., 2010, 53(12), 4701-4719.
[] [PMID: 20513156]
O’Hare, T.; Shakespeare, W.C.; Zhu, X.; Eide, C.A.; Rivera, V.M.; Wang, F.; Adrian, L.T.; Zhou, T.; Huang, W.S.; Xu, Q.; Metcalf, C.A., III; Tyner, J.W.; Loriaux, M.M.; Corbin, A.S.; Wardwell, S.; Ning, Y.; Keats, J.A.; Wang, Y.; Sundaramoorthi, R.; Thomas, M.; Zhou, D.; Snodgrass, J.; Commodore, L.; Sawyer, T.K.; Dalgarno, D.C.; Deininger, M.W.N.; Druker, B.J.; Clackson, T. 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), 401-412.
[] [PMID: 19878872]
Nagar, B.; Hantschel, O.; Young, M.A.; Scheffzek, K.; Veach, D.; Bornmann, W.; Clarkson, B.; Superti-Furga, G.; Kuriyan, J. Structural basis for the autoinhibition of c-Abl tyrosine kinase. Cell, 2003, 112(6), 859-871.
[] [PMID: 12654251]
Gray, N.S.; Fabbro, D. Discovery of Allosteric Bcr – Abl Inhibitors from Phenotypic Screen to Clinical Candidate., (1st ed. ) , 2014; Vol. 548, .
Zhang, J.; Adrián, F.J.; Jahnke, W.; Cowan-Jacob, S.W.; Li, A.G.; Iacob, R.E.; Sim, T.; Powers, J.; Dierks, C.; Sun, F.; Guo, G.R.; Ding, Q.; Okram, B.; Choi, Y.; Wojciechowski, A.; Deng, X.; Liu, G.; Fendrich, G.; Strauss, A.; Vajpai, N.; Grzesiek, S.; Tuntland, T.; Liu, Y.; Bursulaya, B.; Azam, M.; Manley, P.W.; Engen, J.R.; Daley, G.Q.; Warmuth, M.; Gray, N.S. Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors. Nature, 2010, 463(7280), 501-506.
[] [PMID: 20072125]
Hantschel, O. Structure, regulation, signaling, and targeting of abl kinases in cancer. Genes Cancer, 2012, 3(5-6), 436-446.
[] [PMID: 23226581]
Khateb, M.; Ruimi, N.; Khamisie, H.; Najajreh, Y.; Mian, A.; Metodieva, A.; Ruthardt, M.; Mahajna, J. Overcoming Bcr-Abl T315I mutation by combination of GNF-2 and ATP competitors in an Abl-independent mechanism. BMC Cancer, 2012, 12(1), 563.
[] [PMID: 23186157]
Wylie, A.A.; Schoepfer, J.; Jahnke, W.; Cowan-Jacob, S.W.; Loo, A.; Furet, P.; Marzinzik, A.L.; Pelle, X.; Donovan, J.; Zhu, W.; Buonamici, S.; Hassan, A.Q.; Lombardo, F.; Iyer, V.; Palmer, M.; Berellini, G.; Dodd, S.; Thohan, S.; Bitter, H.; Branford, S.; Ross, D.M.; Hughes, T.P.; Petruzzelli, L.; Vanasse, K.G.; Warmuth, M.; Hofmann, F.; Keen, N.J.; Sellers, W.R. The allosteric inhibitor ABL001 enables dual targeting of BCR-ABL1. Nature, 2017, 543(7647), 733-737.
[] [PMID: 28329763]
Agarwal, A.; MacKenzie, R.J.; Pippa, R.; Eide, C.A.; Oddo, J.; Tyner, J.W.; Sears, R.; Vitek, M.P.; Odero, M.D.; Christensen, D.J.; Druker, B.J. Antagonism of SET using OP449 enhances the efficacy of tyrosine kinase inhibitors and overcomes drug resistance in myeloid leukemia. Clin. Cancer Res., 2014, 20(8), 2092-2103.
[] [PMID: 24436473]
Wang, S.; Xie, W.; Wang, D.; Peng, Z.; Zheng, Y.; Liu, N.; Dai, W.; Wang, Y.; Wang, Z.; Yang, Y.; Chen, Y. Discovery of a small molecule targeting SET-PP2A interaction to overcome BCR-ABLT315I mutation of chronic myeloid leukemia. Oncotarget, 2015, 6(14), 12128-12140.
[] [PMID: 25900240]

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