Off-target effects of tyrosine kinase inhibitors: Beauty or the Beast?

Targeted therapy celebrates the concept of ‘designer therapy,’ i.e. designing therapies based on preidentified targets. Tyrosine kinase inhibitors (TKIs), being one of the most successful stories of targeted therapy, have revolutionized the prognosis and management of chronic myeloid leukemia (CML) [1]. Its target, the fusion protein BCR–ABL, beautifully illustrates the three criteria of identifying the target molecule: the molecule must be present in most of the cancer cells; the molecule should not present in most of the normal cells; the molecule should be essential for the persistence and proliferation of cancer cells [2]. Various TKIs have been developed to target the fusion BCR–ABL protein, such as those targeting the inactive conformation (e.g. imatinib, nilotinib) and both the active and inactive conformations (e.g. dasatinib) [3]. However, even with this classic target, modern TKIs remain entangled by off-target effects which result in normal tissue damage [3]. Large granular lymphocytes (LGLs) consist of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) [4,5]. They are essential for innate and acquired immunity against viral infection and neoplasm. However, they are also potential culprits of autoimmunity. The association between LGL expansion and autoimmune diseases is particularly prominent in LGL leukemia, which features a clonal expansion of LGLs [6]. Interestingly, as a manifestation of the off-target effect of TKIs, some TKI treatments are associated with a mono/oligoclonal LGL expansion [7,8]. In this issue of Leukemia and Lymphoma, Powers and his colleagues [9] characterize the molecular signatures of the expanded LGL population in patients with CML treated with TKIs. Moreover, they analyzed the potential mechanisms of this expansion and its association with sideeffects of TKI treatment. Compared to the normal composition of memory repertoire, peripheral T lymphocytes in patients treated with different TKIs all showed a decrease in naive or central memory subsets and an increase in effector/terminal memory subsets, with the trend more prominent in the CD4þ than in the CD8þ population. This is in line with an abnormal T-cell response due to chronic and/or suboptimal stimulation [10]. Consistent with T-cell activation, a clonal T-cell expansion was identified in most of the TKI-treated patients regardless of the TKI used (imatinib, nilotinib, or dasatinib). Interestingly, this universal clonal expansion did not result in universal expansion of LGLs. A significant LGL population was only identified in dasatinib-treated patients. There were correlations between NK-cell or CD8þ T-cell expansion and the presence of adverse reactions, indicating the potential functional importance of LGLs in dasatinib-treated patients. Analyzing peripheral blood samples following different TKI treatments highlighted the molecular ‘royal flush’ that is essential for LGL expansion: interleukin-15 (IL-15) transpresentation, increased levels of plasma platelet derived growth factor BB (PDGF-BB), nuclear factor kB (NF-kB), and T-beta activation and lack of T-regulatory cell (Treg) supervision. The off-target effects of targeted therapy, although not desirable, can sometimes lead to discoveries of novel signaling details otherwise hidden. The work of Powers et al. [9] is important not only for understanding the causes of adverse effects related to TKI treatment but also potentially for improving current T-cell immunotherapy. On the one hand, the correlation between LGL expansion and adverse effects of TKI treatment raised the possibility of