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Journal of Cancer Biology and Research

Tyrosine Kinase Inhibitors in Myeloid Leukemia Therapy - Molecular Mechanisms and Future Challenges

Review Article | Open Access
Article DOI :

  • 1. Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  • 2. Shrewsbury High School, Shrewsbury, Massachusetts, USA
  • 3. Foxborough High School, Foxborough, Massachusetts, USA
  • 4. #Contributed Equally to the Manuscript
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Corresponding Authors
Shaoguang Li, Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
ABBREVIATIONS

PTKs: Protein Tyrosine Kinases; CML: Chronic Myeloid Leukemia; AML: Acute Myeloid Leukemia; TKI: Tyrosine Kinase Inhibitor; FLT3: FMS-like tyrosine kinase 3; HSC: Hematopoietic Stem Cell; LSC: Leukemia Stem Cell; OS: Overall Survival; EFS: Event-Free Survival; CR: Complete Remission.

INTRODUCTION

Protein tyrosine kinases (PTKs) are key regulators for many developmental signaling pathways and are involved in various biological processes [1,2]. They comprise a family of enzymes that catalyze phosphorylation of specific tyrosine residues on target proteins, subsequently leading to conformational changes and activation (or inhibition) of target proteins. Since the first PTK, v-Src encoded by the Rous sarcoma virus oncogene, was identified in 1978, about 90 PTKs have been identified. These PTKs are primarily classified as either RTKs (RTK) [e.g. epidermal growth factor receptors (EGFR), FMS-like tyrosine kinase 3 (FLT3), AXL] or nonRTKs [such as ABL and SRC]. Given the essential roles of PTKs in regulating cellular survival, growth and differentiation, their activities are tightly controlled under physiological conditions. On the other hand, oncogenic mutations of some PTKs constitutively activate their functions, resulting in abnormal cellular growth and differentiation and malignant cell transformation [1]. Thus, inhibition of kinase activities of these PTKs provides an effective strategy for treating many types of cancers associated with abberant PTK activation. In fact, a number of target-specific tyrosine kinase inhibitors (TKIs) have been developed, and often function as homologs of adenosine triphosphate (ATP) to compete for ATP-binding sites, leading to a blockade of kinase activities of both PTKs and donwstream signaling cascades. Importantly, TKIs exhibit significant advantages over chemotherapy and provide a targeted therapy for various types of cancers, including hematologic malignancies.

Hematologic malignancies are a major group of human cancers and include leukemia, lymphoma, and multiple myeloma. Hematologic malignancies are highly heterogeneous in molecular characteristics, thereby bringing huge challenges in clinical management of these diseases. The development of TKIs has significantly improved disease outcomes. Chronic myeloid leukemia (CML), is a myeloproliferative hematopoietic stem cell (HSC) disease that is believed to be derived from an abnormal HSC harboring the Philadelphia (Ph) chromosome [3-5], which is generated by a reciprocal translocation between chromosome 9 and 22 [t(9; 22)(q34; q11)]. The resulting chimeric BCR-ABL fusion oncogene encodes the BCR-ABL oncoprotein, which has constitutive tyrosine kinase activity [3, 6]. BCR-ABL activates numerous downstream pathways that drive CML development by increasing proliferation and reducing apoptosis of BCRABL-expressing cells [7]. The chimeric BCR-ABL oncoprotein constitutes the molecular basis of CML and provided the foundation for the development of imatinib, one of the most effective TKIs in treating human cancers. In fact, the development of TKIs for CML therapy has served as a paradigm for drug development and ignited an era in developing TKIs in the oncology field. Acute myeloid leukemia (AML) is also a heterogeneous clonal disorder and is characterized by uncontrolled expansion and blocked differentiation of myeloid cells. Accumulation of genetic alterations in hematopoietic stem/progenitor cells causes aberrant activation of a series of signaling pathways, ultimately resulting in AML development. Approximately 55% of adult AML cases have cytogenetic abnormalities, often in form of the recurrent gene fusions such as CBFB-MYH11 [inv (16)], PMLRARα [t(15;17)], and AML1-ETO [t(8;21)], and about 30% AML patients carry somatic mutations of the tyrosine kinase FLT3 [8,9]. TKIs targeting FLT3 have been used successfully to treat AML. Thus, we will further review the recent advances on the development of TKIs with an emphasis mainly on two tyrosine kinases: BCR-ABL and FLT3.

TKIs for treating CML harboring the BCR-ABL oncogene

The development of TKIs for BCR-ABL: The development of TKIs targeting BCR-ABL revolutionized CML treatment and has dramatically improved disease management and outcomes. Arsenic was used to reduce the leukocyte count prior to the discovery of the Ph chromosome, but failed to prolong CML patient survival. Busulfan and hydroxyurea, conventional cytotoxic chemotherapeutic agents, were also used in controlling elevated white blood cell counts, but they failed to significantly improve the survival of CML patients [10]. In the 1980s, interferon-α (IFNα) was introduced in for treating CML, and induced both disease remission and prolonged survival in approximately one-third of CML patients [11,12]. Since the chimeric BCR-ABL is a tyrosine kinase, it is an ideal molecular target for designing therapeutic chemical inhibitors [13,14]. Imatinib mesylate (also known as Gleevec, STI-571), the first TKI against BCR-ABL, was approved by the U.S. Food and Drug Administration (FDA) in 2001 and, by 2003, became the front-line therapy for CML in chronic phase [15-17]. Imatinib, along with three generations of anti-BCR-ABL TKIs, has been used to treat CML and has brought long-term remission and near-normal life expectancy to the majority of CML patients.

Mechanisms of TKIs for functional inhibition of BCR-ABL: Imatinib was discovered in a time-consuming in vitro screening of inhibitors for protein kinase C [18, 19]. It was originally shown to be an inhibitor of platelet-derived growth factor receptor and v-ABL protein tyrosine kinase, and later was identified as an inhibitor of c-ABL, BCR-ABL, and c-Kit [19]. The overall structure of the c-ABL kinase domain consists of two lobes, a smaller amino-terminal lobe primarily involving in anchoring and orienting ATP, and the carboxyl-terminal lobe responsible for binding the peptide substrate. The catalytic site lies in a cleft between the two lobes. These two lobes can open or close the cleft by moving toward each other. The open form allows ATP to access the catalytic site, while the closed form brings residues into the catalytic site. Thus, blocking the transition between these two forms inhibits kinase activity. Imatinib binds the cleft between these two lobes and competes for the ATP binding site of the ABL kinase by forming hydrogen bonds, keeping the kinase in an inactive conformation [20]. In addition to the ABL kinase, imatinib also inhibits the platelet derived growth factor receptor (PDGFR) and c-Kit tyrosine kinase [21]. The International Randomized Study of Interferon and STI571 (IRIS) demonstrates that imatinib treatment (400 mg per day) as the standard of care for CML results in reliability and supremacy of hematologic and cytogenetic responses in more than 90% of chronic phrase CML patients [22]. An 8-year follow-up of STI571 showed that the estimated event-free survival rate was 81%, and the overall survival (OS) rate was 93% when only considering CML-related deaths. Furthermore, imatinib significantly increased the 10-year survival rate from 10-20% to 80–90% [22]. Without any doubt, the development of TKIs for CML treatment ignited a new era for targeted therapy in oncology.

The next-generation TKIs for BCR-ABL: Currently, TKIs are the standard treatment for all newly diagnosed patients with CML, and imatinib is the first-generation TKI. To overcome imatinib resistance in CML patients, second (dasatinib, nilotinib, bosutinib) and third-generation (ponatinib) TKIs were also developed (Figure 1). Dasatinib is a dual ABL and SRC family kinase (SFK) inhibitor, and was approved by the FDA in 2007 [23]. It binds to the active and inactive forms of BCR-ABL with higher affinity than imatinib. Dasatinib (100mg daily) has achieved a higher response rate than imatinib (400mg daily) in newly-diagnosed CML chronic phase patients [24,25]. In addition, dasatinib is effective against most imatinib-resistant ABL mutations in patients. Nilotinib is another second-generation TKI with 20 to 50-fold higher affinity for the inactive conformation of BCR-ABL [26,27]. Nilotinib is superior to imatinib as a frontline treatment, but it is associated with a higher rate of complications and side effects (pruritus, hyperglycemia and pancreatitis) [28,29]. Bosutinib is a specific inhibitor for BCR-ABL and SFKs, and was approved by the FDA in 2012 for second-line treatment of CML due to its effectiveness against most imatinib-resistant mutations (F317L and Y253H).

Ponatinib is a third-generation TKI approved by the FDA in 2012. It was designed to target the first and second-generation TKI-resistant BCR-ABLT315I mutant [30]. Ponatinib acts through carbon-carbon triple bond between the methylphenyl and purine groups, allowing it to bind to the T315I mutant. Therefore, ponatinib inhibits both wild type and a variety of mutated BCRABL proteins (e.g. M244V, G250E, Q252H, Y253F/H, E255K/V, F317L, M351T, and F359V) [31]. Ponatinib treatment with a low dose (45mg) can result in faster and deeper response [32].

There are factors to consider when selecting between the aforementioned five TKIs for CML patients to ensure optimal duration and life-quality. In general, imatinib is a safe and costeffective TKI for CML patients in chronic phase; patients with high-risk disease are treated with second/third-generation TKIs. Other factors, including the distinct benefits and variable side effects of each TKI, and individual patient features, are also taken into account [29, 33].

TKIs for AML treatment

Dysregulation of multiple tyrosine kinases such as FLT3, KIT, Janus kinase 2 (JAK2) are found in AML. While some TKIs show efficacy in clinical trials, others are still in early stages of development. Regardless, novel therapies targeting these tyrosine kinases represent a promising strategy in AML therapy, although chemotherapy with anthracycline plus cytarabine remains as a conventional AML therapy.

FLT3 tyrosine kinase inhibitors: FLT3 is a receptor tyrosine kinase (RTK) expressed in hematopoietic progenitor cells and plays an important role in hematopoietic development [34-36]. Upon stimulation with FLT3 ligand, FLT3 dimerizes and undergoes autophosphorylation, leading to activation of downstream pathways including PI3K/Akt and Ras signaling pathways [37,38]. High FLT3 expression is detected in most cases of AML and B-acute lymphoblastic leukemia [39]. Approximately 30% AML patients have FLT3 mutations, mostly as internal tandem duplication (FLT3-ITD, 20-25%) as well as point mutation in the tyrosine kinase domain (FLT3-TKD, 5-10%). These alterations cause ligand-independent FLT3 activation, resulting in constitutive stimulation of downstream signaling pathways. FLT3-ITD is associated with poor prognosis for younger patients with de novo AML and normal cytogenetics [40,41]. Therefore, efforts to develop inhibitors targeting FLT3 have led to successive generations of FLT3 inhibitors over the past decade, including the first-generation FLT3 inhibitors tandutinib, sunitinib, lestaurtinib, sorafenib and midostaurin, and the next generation FLT3 inhibitors quizartinib, crenolanib, and gilteritinib. Based on the mechanism of action, these TKIs can also be categorized into: type I TKIs (including midostaurin, gilteritinib and crenolanib) that bind the activation loop or ATPbinding pocket of the FLT3 receptor in the active conformation, and are active against FLT3-ITD and TKD; and type II (including sorafenib and quizartinib) that bind the ATP-binding pocket of FLT3 receptor in the inactive conformation and are active against FLT3-ITD but not TKD. Below, we describe some representative TKIs for FLT3 (Figure 1).

Midostaurin is an oral, first-generation TKI that targets both FLT3-ITD and -TKD mutations, and also shows effectiveness in suppressing PKC, c-Kit, VEGFR, and PDGFR-β. It was approved in 2017 by the FDA for the management of relapsed/refractory AML patients with FLT3 mutations, and was recently accepted as a front-line therapy for newly diagnosed AML patients with FLT3 mutations, systemic mastocytosis, and related disorders due to its inhibitory effect on c-Kit bearing a D816V mutation [42,43]. Based on the RATIFY study, midostaurin combined with standard chemotherapy, followed by the maintenance therapy for 1 year, significantly improved both overall survival (OS) (74.7 months vs. 25.6 months, p = 0.009) and event-free survival (EFS) (8.2 months vs 3.0 months, p = 0.002) but not complete remission (CR) compared to chemotherapy alone [44]. Midostaurin also reduces relapse in FLT3-mutant AML [45]. In a phase II study, midostaurin treatment reduced blast counts 50% or more in 71% patients with R/R AML or high-risk MDS with FLT3 mutations [46].

Sorafenib is an oral multi-kinase inhibitor for RAF-1, VEGFR, c-Kit, PDGFR, ERK and FLT3. Beyond inhibiting kinase activity, sorafenib stimulates IL-15 secretion and increases the survival of AML patients [47]. Moreover, sorafenib also inhibits SRCSTAT3 pathways. Sorafenib monotherapy in R/R AML has marked FLT3-ITD inhibition, good tolerability, and about 11.1% CR rate. Combinations of sorafenib with other agents were also investigated. For instance, azacitidine plus sorafenib showed a CRc of 43% and mOS of 6.2 months in 37 R/R and untreated unfit AML patients (93% were FLT-ITD) [48]. The use of combinations of sorafenib with intensive schemes of induction and consolidation in untreated AML was widely investigated and showed a trend to lower survival in AML with FLT3-ITD [49- 51]. Recently, an open-label, multicenter, randomized phase 3 trial was performed to investigate the efficacy and tolerability of sorafenib maintenance post-transplantation [52]. About 202 AML patients with FLT3-ITD receiving allogeneic HSC transplantation (allo-HSCT) were randomly assigned to sorafenib maintenance (400 mg orally twice daily) or non-maintenance (control) at 30- 60 days post-transplantation; the 1-year cumulative incidence of relapse was 7.0% in the sorafenib group and 24.5% in the control group. Within 210 days post transplantation, sorafenib treatment did not affect adverse events including infections (25% vs 24%), acute graft-versus-host-disease (GVHD; 23% vs 21%), chronic GVHD (18% vs 17%), and hematological toxicity (15% vs 7%). This study indicates that post-transplantation maintenance therapy by sorafenib reduces relapse and is well tolerated in AML with FLT3-ITD. In another randomized, placebo-controlled, double-blind phase II trial (SORMAIN), 83 adult patients with AML with FLT3-ITD in complete hematologic remission after HCT were randomly assigned to receive for 24 months either sorafenib (n = 43) or placebo (n = 40). The 24-month relapsefree survival (RFS) was 85.0% with sorafenib versus 53.3% with placebo [53]. Together, these studies indicate that sorafenib prevents AML relapse after allo-HSCT.

Gilteritinib is an oral potent type I FLT3 inhibitor, and is also effective against AXL. In a phase 3 trial, 371 R/R AML patients with FLT3 mutations were randomly assigned to receive either gilteritinib (120 mg daily) or salvage chemotherapy. The median overall survival (mOS) in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months). The median EFS was 2.8 vs 0.7 months, for gilteritinib and chemotherapy groups respectively, and the CR percentage of patients with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group [54]. This indicates that gilteritinib resulted in significantly longer survival and higher remission rate than salvage chemotherapy among patients with relapsed or refractory FLT3-mutated AML [54]. This work led to the approval of gilteritinib by the FDA and EMA for R/R FLT3-mut AML.

Quizartinib is a potent, selective, second-generation FLT3 inhibitor shown to reduce blast number in the bone marrow of a substantial number of patients. A high complete remission response rate and overall survival in R/R AML patients with FLT3-ITD were also observed [55]. Several clinical trials, in which quizartinib was combined with conventional chemotherapy for frontline therapy or as a maintenance therapy following hematopoietic stem cell transplant, are ongoing. Quizartinib exhibited low nanomolar potency, high selectivity, and sustained inhibition of FLT3 kinase activity in leukemic cells of AML patients when compared to sorafenib and other FLT3 inhibitors [56].

FLT3 inhibitors are now important for treating a large subset of high-risk R/R patients, as a frontline for the treatment-naïve, or for maintenance after allo-HSCT. Recent randomized trials of TKIs, including gilteritinib, quizartinib, and sorafenib, predict an even wider use of FLT3 inhibitors in the future.

Tyrosine kinase inhibitors for AXL: The RTK AXL is emerging as a key player in tumor progression and metastasis, and its expression correlates with poor survival in a plethora of cancers. AXL belongs to the TYRO3, AXL, and MERTK (TAM) subfamily of RTKs. TAM family receptors are overexpressed in a wide variety of human cancers in which they provide tumor cells with a survival advantage [57]. TAM RTK activation mechanisms are unique. Growth arrest specific 6 (GAS6) is the ligand of AXL, and also binds to TYRO3 and MERTK. TAM activation stimulates downstream MEK, PI3K/AKT, and ERK pathways, and regulates cytoskeletal function, intracellular signaling, and gene expression (Figure 1) [57].

High AXL and GAS6 expression has been observed in AML and CML, and is associated with poor prognosis in AML [58]. A recent study showed that AXL and GAS6 expression is highly elevated in primitive AML cells, particularly in stem/progenitor cells [59]. In AML cells, RNA m6 A demethylase ALKBH5 affects mRNA stability of RTK AXL in an m6 A-dependent manner [60]. The AXL inhibitor ONO-7475 kills FLT3-mutant AML cells [61]. A potent selective AXL inhibitor, SLC391, was recently developed [59], and showed favorable pharmaceutical properties and efficacy in preclinical patient-derived xenotransplantation (PDX) models of AML. Additionally, AXL inhibition sensitized AML stem/ progenitor cells to treatment with the BCL2 inhibitor venetoclax, accompanied by strong synergistic effects in vitro and in PDX models [59]. A pharmacologic AXL inhibitor, AXL-Fc, inhibited cell growth, induced cell-cycle arrest and apoptosis, and relieved a block in myeloid differentiation of FLT3-ITD+ AML in vitro, suggesting that AXL contributes to the pathogenesis of FLT3-ITD+ AML by regulation of constitutive FLT3 activation [62]. Finally, AXL is required for resistance of FLT3-ITD+ AML cells to the FLT3 inhibitor [63]. Thus, inhibition of AXL activation may overcome resistance to FLT3-targeted therapy in FLT3-ITD+ AML.

Current challenges in treating myeloid leukemias with TKIs

Although some TKIs have achieved a success in induction of clinical remission of leukemias, the development TKI resistance and the existence of resistant leukemia stem cells (LSCs) pose challenges. For instance, discontinuation of TKI treatment results in early molecular relapse in some CML cases, and development of BCR-ABL mutations induces TKI resistance in some CML patients [64]. Also, it has been shown that TKIs are unable to eradicate the primitive quiescent CML LSCs [65-67]. The survival of primitive LSCs is independent of BCR-ABL kinase activity, and other signaling pathways might be responsible for the maintenance and survival of LSCs [68]. Therefore, targeting essential components in LSCs in addition to tarteting BCR-ABL with TKIs should prove more effective in treating myeloid leukemias.

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Received : 23 May 2023
Accepted : 27 Apr 2023
Published : 27 Apr 2023
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