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Logo of jbcThe Journal of Biological Chemistry
 
J Biol Chem. 2015 April 17; 290(16): 10568–10569.
PMCID: PMC4400363

Interleukin-2-inducible T-cell Kinase (ITK) Targeting by BMS-509744 Does Not Affect Cell Viability in T-cell Prolymphocytic Leukemia (T-PLL)

Zhong et al. (1) characterize PRN694, a dual inhibitor of ITK and resting lymphocyte kinase (RLK). They demonstrate activity against T-cell receptor (TCR) signaling in T-PLL and suggest a therapeutic application. However, an actual TCR dependence of T-PLL is not established (2), and cytotoxic consequences of inhibited kinase activation in T-PLL cells by PRN694 (1) or various other ITK inhibitors (3) are not reported.

In a comparative meta-analysis of expression profiling data across mature T-cell leukemias/lymphomas, we characterize T-PLL as a category with a prominent signature of TCR signaling components, including ITK (4). However, we describe here the surprisingly low in vitro efficacy of the ITK (not RLK) inhibitor BMS-509744 in T-cell leukemia lines (Fig. 1, A–D) and primary T-PLL cells (Fig. 1E). The assessment of target mRNA levels of 71 T-PLL compared with normal T-cells revealed that ITK was down-regulated; RLK expression was largely unaltered (Fig. 1F).

FIGURE 1.
BMS-509744 does not affect the viability of malignant T-cell lines and primary T-PLL cells. A, HH cells (2 independent experiments) were treated with BMS-509744 for 24 and 48 h. Apoptosis was measured using AnnV/7AAD flow cytometry. HH cells did only ...

Although we could not perform a head-to-head comparison of both inhibitors, evaluations of the potency of such ITK targeting have to consider the effects of individual drug selectivities (5). The affinity of PRN694 to ITK is reported to be higher than for BMS-509744 (IC50 values: 0.3 nm versus 15 nm) (5). Addressing potential cross-kinase stand-in functions, e.g. of RLK for ITK, might be another beneficial property of PRN694. Moreover, PRN694 targets additional driver kinases of T-PLL, including JAK3 (IC50 = 30 nm) (6).

Overall, the success of BTK inhibition, as in B-cell chronic lymphocytic leukemia, is likely not easily translatable to ITK targeting in T-PLL. However, the limited therapeutic options in the notoriously refractory T-PLL warrant intensified approaches that address the unique biology of the transformed T-cell, i.e. TCR-specific kinases.

References

1. Zhong Y., Dong S., Strattan E., Ren L., Butchar J. P., Thornton K., Mishra A., Porcu P., Bradshaw J. M., Bisconte A., Owens T. D., Verner E., Brameld K. A., Funk J. O., Hill R. J., Johnson A. J., Dubovsky J. A. (2015) Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. J. Biol. Chem. 290, 5960–5978 [PMC free article] [PubMed]
2. Herling M., Patel K. A., Teitell M. A., Konopleva M., Ravandi F., Kobayashi R., Jones D. (2008) High TCL1 expression and intact T-cell receptor signaling define a hyperproliferative subset of T-cell prolymphocytic leukemia. Blood 111, 328–337 [PubMed]
3. Vargas L., Hamasy A., Nore B. F., Smith C. I. E. (2013) Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases. Scand. J. Immunol. 78, 130–139 [PubMed]
4. Warner K., Weit N., Crispatzu G., Admirand J., Jones D., Herling M. (2013) Cell receptor signaling in peripheral T-cell lymphoma - a review of patterns of alterations in a central growth regulatory pathway. Curr. Hematol. Malig. Rep. 8, 163–172 [PubMed]
5. Charrier J. D., Knegtel R. M. A. (2013) Advances in the design of ITK inhibitors. Expert Opin. Drug Discov. 8, 369–381 [PubMed]
6. Kiel M. J., Velusamy T., Rolland D., Sahasrabuddhe A. A., Chung F., Bailey N. G., Schrader A., Li B., Li J. Z., Ozel A. B., Betz B. L., Miranda R. N., Medeiros L. J., Zhao L., Herling M., Lim M. S., Elenitoba-Johnson K. S. J. (2014) Integrated genomic sequencing reveals mutational landscape of T-cell prolymphocytic leukemia. Blood 124, 1460–1472 [PubMed]

Articles from The Journal of Biological Chemistry are provided here courtesy of American Society for Biochemistry and Molecular Biology