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Class Effects of Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia

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Class Effects of Tyrosine Kinase Inhibitors in the Treatment of Chronic Myeloid Leukemia Leukemia (2009) 23, 1698–1707 & 2009 Macmillan Publishers Limited All rights reserved 0887-6924/09 $32.00 www.nature.com/leu SPOTLIGHT REVIEW Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia FJ Giles1, M O’Dwyer2 and R Swords1 1Institute for Drug Development, Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio, San Antonio, TX, USA and 2Department of Hematology, University College Hospital, Galway, Ireland Tyrosine kinase inhibitors have revolutionized the treatment of during treatment.8–11 Several strategies are available to treat chronic myeloid leukemia (CML), offering patients several imatinib-resistant patients, including imatinib dose escalation, targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the avail- dose adjustment based on pharmacokinetic assessments and the ability of imatinib, nilotinib and dasatinib, physicians must use of novel TKIs (Figure 1, Table 1). weigh the efficacy and safety profile of each agent when Nilotinib and dasatinib are potent inhibitors of BCR-ABL that choosing the best therapeutic option for individual patients. are US Food and Drug Administration approved for the SPOTLIGHT Each agent targets tyrosine kinases within the cell uniquely to treatment of patients resistant to, or intolerant of, prior therapy, cause the desired antiproliferative effect. In addition to inhibit- including imatinib. These second-generation TKIs have shown ing the BCR-ABL kinase, imatinib and nilotinib target the same 12–14 array of other tyrosine kinases, including c-KIT and platelet- efficacy in all imatinib-resistant or -intolerant CML patients. derived growth factor receptor (PDGFR), albeit with differing Thus far, nilotinib and dasatinib appear to be similar with regard 15 potencies. While targeting BCR-ABL with the highest potency to clinical efficacy, although they display differential safety among approved agents in CML, dasatinib also targets a broad profiles.16 Other new kinase inhibitors are in early clinical array of off-target kinases, including SRC family members, trials as alternatives to imatinib therapy, including bosutinib, PDGFR and EPHB4. The differences in kinase inhibition profiles MK-0457 and INNO-406 (Figure 1, Table 1). Larger prospective, among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the randomized studies are needed to determine the place of these various kinases inhibited by imatinib, nilotinib and dasatinib, new therapies in the treatment algorithm of CML. However, the and describes the potential impact of kinase inhibition on the potential for increased potency of these drugs could eventually efficacy and safety of each agent. lead to their replacement of imatinib as first-line CML therapy. Leukemia (2009) 23, 1698–1707; doi:10.1038/leu.2009.111; Although these new therapies are already changing the land- published online 28 May 2009 scape of CML therapy, it is important to distinguish the Keywords: CML; imatinib; nilotinib; dasatinib; TKI; BCR-ABL differences between these agents regarding target kinase profile, safety and efficacy. This article will review the similarities and differences in the kinase inhibition profiles of imatinib, nilotinib, dasatinib and newer BCR-ABL kinase inhibitors, with a focus on the safety of each agent. Although no randomized clinical Introduction trials have been conducted comparing nilotinib and dasatinib treatments, one must use the data from the available studies to The introduction of the small tyrosine kinase inhibitor (TKI), make an informed choice between the two agents for patients imatinib, has revolutionized the treatment of chronic myeloid who have become resistant or intolerant to imatinib therapy. leukemia (CML).1 Imatinib is a relatively specific inhibitor The following sections will highlight pre-clinical and clinical of BCR-ABL, the gene product of the t(9;22) chromosomal data to assist in choosing between the currently available translocation event that forms the Philadelphia chromo- second-generation agents. some characteristic of CML and some acute lymphocytic leukemias.2,3 The fusion of BCR-ABL results in the constitutive activity of the ABL tyrosine kinase, which ultimately drives Differential kinase inhibition profiles of TKIs in CML transformation of hematopoietic progenitor cells. treatment Imatinib was approved by the US Food and Drug Adminis- tration in 2002 for the first-line treatment of CML based on Inhibition of the BCR-ABL tyrosine kinase is considered to be the its high cytogenetic and molecular response rates, long-term underlying mechanism of clinical activity of imatinib, nilotinib efficacy and superior tolerability over interferon (IFN)-based and dasatinib in the treatment of CML. As the first-generation therapy.4,5 Imatinib is widely accepted as the standard therapy TKI in this class of agents, imatinib inhibits BCR-ABL, albeit to a for newly diagnosed chronic-phase CML patients in addition to lesser extent than nilotinib or dasatinib. Imatinib also inhibits all CML patients who have failed stem cell transplant or IFN-a c-KIT and platelet-derived growth factor receptor (PDGFR) at therapy.6,7 Imatinib serves as a model for the utility of targeted clinically relevant concentrations (Table 1). Nilotinib inhibits agents in the treatment of cancer. For a relatively few CML most imatinib-resistant BCR-ABL forms, except T315I, in vitro at patients, resistance to imatinib is present before, or develops 17 concentrations approved for and tested in patients. Nilotinib is 30-fold more potent than imatinib at inhibiting BCR-ABL Correspondence: Dr FJ Giles, CTRC at The UT Health Science Center (Table 2).18,19 Early data on nilotinib in newly diagnosed CML at San Antonio, Institute for Drug Development, 7979 Wurzbach patients suggest clinical activity with the potential to exceed Road, San Antonio, TX 78229, USA. 20 E-mail: [email protected] first-line imatinib efficacy, pending longer follow-up data. 18,19 Received 19 March 2009; revised 6 April 2009; accepted 17 April Similar to imatinib, nilotinib inhibits c-KIT (IC50 ¼ 90 nM) 13,19 2009; published online 28 May 2009 and PDGFR (IC50 ¼ 72 nM). Nilotinib also inhibits the Class effects of TKIs in the treatment of CML FJ Giles et al 1699 ABL-related kinase ARG, DDR1 kinase, the oxidoreductase 325-fold more potency than imatinib at inhibiting BCR-ABL NQO2,20,21 and has some activity against the ephrin receptor (Table 2).14 Dasatinib also inhibits c-KIT and PDGFR with EPHB4, but displays no activity against the Src family of greater potency, and has a broad range of inhibitory activity kinases.13,22 Similar to nilotinib, dasatinib also inhibits most against a number of other tyrosine kinases (Table 2), including imatinib-resistant BCR-ABL forms, except T315I, in vitro.14,23 the ephrin receptor tyrosine kinase, Src and Src family kinases However, it displays greater inhibition, with approximately (FGR, FYN, HCK, LCK, LYN and YES).22,24 Lack of selectivity in binding Src family kinases probably derives from the fact that, unlike imatinib and nilotinib, dasatinib binds to the active conformation of the ABL kinase domain. In its active conforma- tion, ABL bears remarkable structural resemblance to the Src family kinases.25 Although both nilotinib and dasatinib have shown activity against a range of BCR-ABL kinase mutations, there exist a number of specific mutations that are less sensitive to each of these agents. For nilotinib, these mutations include E255K/V, Y253H, F359V and T315I, and for dasatinib, these mutations include Q252H, E255K/V, F317L, V299L and T315I.26–28 The relationship of kinase inhibition profile with safety Wild-type ABL inhibition: cardiac events All currently approved TKIs for CML treatment inhibit wild-type ABL kinase. ABL is a key mediator of normal cardiac function and is expressed in the cardiac and other tissues (Figure 2). A link between the imatinib inhibition of ABL and cardiac events was first suggested by Kerkela et al.29 In this retrospective study, 10 subjects with normal baseline cardiac function developed left ventricular dysfunction during imatinib therapy. Correlative studies in mice and cell lines revealed that imatinib-induced inhibition of ABL led to an endoplasmic reticulum stress response, collapse of the mitochondrial membrane potential, Table 2 IC50 values for bosutinib, imatinib, dasatinib and nilotinib against BCR-ABL expressed in Ba/F3-transfected cells108 IC50 values (nM) Bosutinib Imatinib Dasatinib Nilotinib BCR-ABL 41.61 527 1.83 17.69 Figure 1 Structures of current and investigational tyrosine kinase inhibitors for the treatment of CML.100 Adapted from Weisberg et al.106 Adapted from Redaelli et al.108 Table 1 Novel tyrosine kinase inhibitors currently in clinical trials for the treatment of CML105 SPOTLIGHT Tyrosine kinase inhibitor Kinase targets Drug Drug Company administration development status Imatinib (STI571) ABL, PDGFR, c-KIT Oral Approved Novartis Pharmaceuticals, San Carlos, CA, USA Dasatinib (BMS-34825) ABL, PDGFR, c-KIT, FGR, FYN, HCK, LCK, Oral Approved Bristol-Myers Squibb, LYN, SRC, YES, EPHB4 New York, NY, USA Nilotinib (AMN 107) ABL, PDGFR, c-KIT, ARG, EPHB4 Oral Approved Novartis, San Carlos, CA, USA Bosutinib (SKI-606) ABL, FGR, LYN, SRC Oral Phase II Wyeth, Madison, NJ, USA INNO-406 (NS-187) ABL, LYN, PDGFR, c-KIT Oral Phase I Innovive Pharmaceuticals, New York, NY, USA AZD0530 Src family kinases Oral Phase II AstraZeneca, Washington, DC, (solid tumors) USA MK-0457 (VX-680) Aurora kinases, FLTE, JAK2, ABL, T315I ABL Intravenous Phase II Merck & Co., Inc., Whitehouse Station, NJ, USA PHA-739358 Aurora A, B and C Oral Phase II Nerviano Medical Sciences, Nerviano, Italy Abbreviation: CML, chronic myeloid leukemia. Adapted from Weisberg et al.106 Leukemia Class effects of TKIs in the treatment of CML FJ Giles et al 1700 SPOTLIGHT Figure 2 ABL signaling and inhibition in cardiomyocytes.101 In cardiomyocytes, imatinib induces ER stress, leading to the activation of the PKR- like ER kinase (PERK) and IRE1 pathways, and to the overexpression of protein kinase Cd (PKCd).
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