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Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
Laboratory of Lymphocyte Signaling and Oncoproteome, Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, and Excellence Cluster for Cellular Stress Response and Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
) 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 (
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 (
). 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 1BMS-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 respond to BMS-509744 by apoptosis at high (micromolar) concentrations. The percentage of viable cells relative to vehicle control is shown. B, immunoblots. HH cells were treated for 48 h with different dosages of BMS-509744. Although the basal phosphorylation levels of ERK1/2 remain unaffected, the phosphorylation of PLCγ was decreased with higher dosages of BMS-509744. C, Jurkat cells (2 independent experiments) were treated with BMS-509744 for 24 h. Apoptosis was measured using AnnV/7AAD flow cytometry. Jurkat cells did not undergo cell death at marked degrees after BMS-509744 treatment. D, Jurkat cells were treated for 24 h with different dosages of BMS-509744. Comparable to HH cells, the phosphorylation of PLCγ was decreased only with higher dosages of BMS-509744. E, primary T-PLL cells (n = 5 cases) were treated ex vivo with BMS-509744 for 24 and 48 h. Apoptosis was measured using AnnV/7AAD staining by flow cytometry. BMS-509744 did not affect tumor cell viability. F, gene expression levels of ITK (left) and RLK (right) in CD3 positive pan T-cells, enriched from 10 healthy donors, were compared with those in 71 T-PLL cases (>97% tumor cell purity) using HumanHT-12 v4 Expression BeadChip arrays. Log2 expression levels are shown.
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 (
). 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) (
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
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.
Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694.
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