Non-tyrosine kinase inhibitor-targeting of BCR–ABL expressing cells

Th e introduction in clinical practice of tyrosine kinase inhibitors (TKIs) targeting the oncogenic BCR – ABL protein has had a dramatic impact on the natural history of chronic myeloid leukemia (CML) and, in many cases, has transformed this previously fatal leukemia into a manageable chronic condition. Although in some epidemiological studies the estimated life expectancy of patients with chronic phase CML (CML-CP) receiving TKIs approaches that of the general population, approximately 30% of patients will either fail to respond to imatinib mesylate or will develop secondary resistance, with disease progression after an initial response [1,2]. Th is has necessitated a better understanding of the mechanisms by which leukemia cells develop resistance to TKIs and the design of approaches to identify and, possibly, predict emergence of such resistance. Over the last decade, substantial advances have been made in delineating molecular mechanisms of imatinib resistance in vitro and in vivo . Among them are overexpression of BCR – ABL, mutations in BCR – ABL, activation of alternative survival pathways and alterations in drug effl ux transporters [3 – 5]. However, the presence of a particular mechanism of resistance in leukemic cells does not necessarily establish that such a mechanism operates alone, and it is possible that more than one mechanism and pathways may be involved in the emergence of resistance and clinical progression in a given patient. Because of the continuous emergence of new mechanisms of resistance of BCR – ABL transformed cells, several rationally designed kinase inhibitors are currently in various stages of clinical development. The most advanced third-generation TKI, ponatinib, is active against the T315I-BCR – ABL mutation [6,7]. Beyond BCR – ABL, this TKI also targets and inhibits other kinases, including FLT3 (fms-like tyrosine kinase receptor-3), FGFR (fibroblast growth factor receptor), VEGFR (vascular endothelial growth factor receptor), c-Kit and PDGFR (platelet derived growth factor receptor) [6,7]. Aurora kinase inhibitors such as AT9283 and danusertib are also currently in clinical trials [8], while other inhibitors currently undergoing preclinical or clinical evaluation include the “ switch pocket inhibitor ” DCC-2036 [9] and GNF-2, an allosteric, non-adenosine triphosphate (ATP) competitive BCR – ABL inhibitor, which specifically binds at the myristoyl binding cleft of BCR – ABL [10]. There are also compounds that are believed to exhibit antileukemic effects by causing degradation of BCR – ABL. Among them is PEITIC (phenylethyl isothiocyanate), a natural compound found in vegetables, which exhibits antileukemic effects in vitro via induction of oxidative stress, leading to BCR – ABL degradation [11]. With the emergence of resistance to TKIs, the development of new drugs for the treatment of CML and Philadelphia chromosome positive (Ph ) acute lymphoblastic leukemia (ALL) continues to be relevant and important. In this issue of Leukemia and Lymphoma , Pillai et al . demonstrate that treatment of K562 cells with 8-aminoadenosine results in an increase in 8-amino-ATP, accompanied by a decline in the endogenous ATP pool [12]. Th e authors also demonstrate that 8-amino-adenosine inhibits BCR – ABL mRNA synthesis, suggesting a mechanism by which this agent may generate antileukemic responses, by blocking expression of the BCR – ABL oncoprotein. Such eff ects apparently resulted in increased apoptosis of transformed cells and modest enhancing eff ects on the generation of imatinib mesylate-responses in sensitive cells. Although the results of this study are premature to enable conclusions to be drawn regarding the potential utility of 8-amino-adenosine, the demonstration of suppression of BCR – ABL mRNA expression by this agent is interesting. Such fi ndings raise the possibility of future combinations of agents that suppress BCR – ABL mRNA expression with TKIs or other agents that target key survival pathways in leukemia cells, and this remains to be addressed in further preclinical studies.