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Short-term intense Bcr–Abl kinase inhibition with nilotinib is adequate to trigger cell death in BCR-ABL+ cells

Leukemia volume 23, pages 1205–1206 (2009)Cite this article

Imatinib mesylate (Glivec, Novartis Pharmaceutical, Basel, Switzerland), a small molecule tyrosine kinase inhibitor, is the first line of treatment for newly diagnosed chronic myeloid leukemia chronic phase patients. Earlier studies have suggested that continuous Bcr–Abl kinase inhibition by imatinib mesylate is a prerequisite for effective response.1 Subsequent clinical pharmacokinetic and pharmacodynamic studies of imatinib mesylate showed significant responses with trough doses above 1 μM.2 These set the paradigm for continuous Bcr–Abl kinase inhibition by imatinib mesylate, as the optimal strategy in chronic myeloid leukemia therapy. Recently Shah et al.3 reported that transient potent Bcr–Abl kinase inhibition with 100 nM dasatinib is sufficient to commit Bcr–Abl+ cell lines to irreversible cell death. They also showed that transient intense and continuous partial Bcr–Abl kinase inhibition trigger equivalent cell death, showing the trade-off between duration and depth of kinase inhibition. This phenomenon was elicited in vitro with a concentration of imatinib (32.5 μM) far above that achievable pharmacologically, although the kinase inhibitory dose of dasatinib (100 nM) is clinically achievable.3, 4 Despite reactivation of Bcr–Abl kinase within 8 h of dasatinib dosing, a randomized clinical trial comparing once versus twice a day dosing schedule of this drug showed equivalent responses in chronic myeloid leukemia chronic phase patients.5 Nilotinib, a second generation tyrosine kinase inhibitor, is 30 times more potent than imatinib against Bcr-Abl kinase. However, nilotinib is less potent than dasatinib and has a more restricted spectrum of kinase inhibition. Moreover, nilotinib's in vivo half-life is 15 h, in contrast to that of dasatinib, which is 3–5 h. We, therefore, sought to assess the effect of short-term exposure to therapeutically achievable concentrations of nilotinib on Bcr–Abl kinase inhibition and cell death in chronic myeloid leukemia cell lines.

Shah et al.3 suggested that cell death triggered by short-term culture with 100 nM dasatinib or 32.5 μM imatinib was related to specific Bcr–Abl kinase inhibition activity, rather than the combined effect of blockade of Bcr–Abl and Src family or other kinases. However, dasatinib and very high-dose imatinib inhibits a broad range of kinases, hence a critical role for off-target effects could not be ruled out. Our current study clarifies the central role of Bcr–Abl kinase inhibition. Nilotinib is more potent than imatinib against Bcr–Abl kinase, but unlike dasatinib, it has minimal activity against Src kinases (Manley PW et al. AACR annual meeting 2007, Vol. 48, abstract 3249). Dasatinib is approximately 10 times more potent than nilotinib and the cell death triggered by short-term 100 nM dasatinib and 1 μM nilotinib (equipotent concentration) are similar. Thus, our results and those of Shah et al. suggest that cell death triggered by short-term intense kinase inhibition with nilotinib or dasatinib is likely to be specifically due to Bcr–Abl kinase inhibition, rather than off-target effect.

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Authors and Affiliations

  1. Division of Haematology, Centre for Cancer Biology, IMVS, Adelaide, Australia

    D K Hiwase, D L White, V A Saunders, S Kumar, J V Melo & T P Hughes

  2. Department of Medicine, Faculty of Health Science, University of Adelaide, Adelaide, Australia

    D K Hiwase, D L White, S Kumar, J V Melo & T P Hughes

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  1. D K Hiwase
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Correspondence to T P Hughes.

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Hiwase, D., White, D., Saunders, V. et al. Short-term intense Bcr–Abl kinase inhibition with nilotinib is adequate to trigger cell death in BCR-ABL+ cells. Leukemia 23, 1205–1206 (2009). https://doi.org/10.1038/leu.2009.45

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