Tyrosine kinase inhibition in acute myeloid leukemia

Extensive work by many groups over the last two decades has established that tyrosine kinases play critical roles in the proliferation and survival of myeloid leukemia cells. Targeting pathways activated by dysregulated tyrosine kinases in acute myeloid leukemia (AML) or chronic myeloid leukemia (CML) has been a major focus of clinical efforts for the development of novel therapeutic agents and approaches [1,2]. This has led to major therapeutic advances in CML, with the development of first- or second-generation tyrosine kinase inhibitors that block the activity of the BCR–ABL tyrosine kinase, including imatinib mesylate, nilotinib, dasatinib and bosutinib [2–4]. The impact of targeted tyrosine kinase inhibition in CML has been remarkable, and has dramatically changed the outcome of patients diagnosed with CML. Despite this, there has been emergence of resistance to the effects of tyrosine kinase inhibitors, associated with BCR–ABL mutations or other mechanisms downstream of BCR–ABL [5]. However, agents such as ponatinib, which inhibits the T315I mutation [6], or other drugs that target elements of cellular pathways downstream of BCR–ABL [7], or the recently Food and Drug Administration (FDA)-approved omacetaxine [8], may provide future approaches to overcome resistance in CML and/or Philadelphia chromosome positive [Ph(+)] acute lymphoblastic leukemia (ALL).

Despite the substantial advances in our understanding of the molecular mechanisms accounting for the pathogenesis and pathophysiology of AML, new targeted agents for the treatment of AML have not so far had a substantial impact on the management of this acute leukemia. This is in sharp contrast with the therapeutic evolution seen in CML in recent years. Efforts at the pre-clinical and clinical level, aimed to develop drugs that target signaling cascades critical for leukemic cell survival, such us the mammalian target of rapamycin (mTOR) pathway [9] or other cellular cascades [10], are currently ongoing. Tyrosine kinase inhibitors are also of potential clinical interest for the treatment of AML, especially as tyrosine kinases such as the FMS-like tyrosine kinase 3 (FLT3) are emerging as potential therapeutic targets [1]. This has led to clinical trials in AML of different multikinase inhibitors such as sorafenib [11,12] and AC 220 [13] that inhibit, among other targets, FLT3. Although efforts with these and other agents such as lestaurtinib and midostaurin [1] may ultimately have an impact on the treatment of AML, the development of other new drugs may provide additional opportunities and/or different toxicity profiles and lead to desperately needed new therapeutic approaches for the treatment of acute leukemias.

In the current issue of the journal, Bourrié et al. [14] report on a new tyrosine kinase inhibitor, SAR103168, with activity against both AML cell lines and primary AML cells in vitro [14]. In initial studies to establish the specificity of SAR103168, the authors found inhibition of Src family kinases and several other kinases, including ABL, vascular endothelial growth factor receptor (VEGFR), Tie2, platelet derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR) [14]. Notably, SAR103168 had no activity against FLT3 and other kinases whose functions are known to promote leukemic cell proliferation and/or survival, such c-KIT, Aurora and others. In further studies using this inhibitor, the authors demonstrated potent inhibitory effects on the KG1 leukemia cell line and on primary leukemic progenitors from patients with AML. It should be noted that a large number of AML patient samples were studied, and the inhibitor was found to exhibit inhibitory effects in the majority of them [14]. Interestingly, such inhibitory effects were unrelated to the presence of FLT3 mutations or FLT3-internal tandem duplication (ITD). In addition, the authors were able to demonstrate substantial inhibitory effects in vivo using mice in which different AML cell lines were implanted.

Altogether, the findings of the study by Bourrié et al. [14] establish that SAR103168 exhibits potent antileukemic effects in vitro and in vivo and raise the possibility that this inhibitor may prove to be useful for the treatment of AML. The authors also indicated in the discussion of their findings that a phase I trial was conducted in patients with refractory acute leukemias or high-risk myelodysplastic syndrome (MDS), and that the study was completed prior to reaching a maximum tolerated dose (MTD) [14]. Although the results of that phase I study have not been published at this time, it will be of high interest to observe the outcome of that trial and any possible follow-up clinical development of this drug for the treatment of AML and/or other hematological malignancies.

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