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Gefitinib potentiates myeloid cell differentiation by ATRA

Leukemia volume 22, pages 1624–1627 (2008)Cite this article

Acute myeloid leukemias (AMLs) are characterized by a variety of genetic defects that contribute to the failure of these cells to undergo differentiation to mature granulocytes or monocytes/macrophages. A primary consequence of this failure to differentiate is the accumulation of proliferative blasts in the bone marrow and peripheral blood. In the case of one subtype of AML, acute promyelocytic leukemia (APL; FAB M3), differentiation can be induced by all-trans retinoic acid (ATRA), a treatment that is curative for many acute promyelocytic leukemia patients.1, 2 However, ATRA has not proven to be effective in the treatment of other subtypes of AML, underscoring the need to identify new compounds that can either induce differentiation as monotherapies or enhance the efficacy of ATRA therapy. Here we report that the tyrosine kinase inhibitor gefitinib markedly enhances ATRA-induced differentiation in myeloid cell lines.

We and others have shown that ATRA-induced monocytic and granulocytic differentiation is dependent on activation of serine/threonine kinases in the mitogen-activated protein kinase kinase/extracellular-regulated kinase (MEK/ERK) signaling pathway.3 In addition, we have reported that pharmacologic inhibition of Src family kinases results in enhancement of ATRA-induced myeloid differentiation.4 These results indicate that tyrosine kinases in the Src family kinase family act as negative regulators of ATRA-induced differentiation. Recently, Stegmaier et al.5 have shown that the pharmacologic inhibitor gefitinib stimulates differentiation of the myeloid cell lines HL-60, Kasumi-1 and U937. Gefitinib is a small molecule inhibitor of the epidermal growth factor receptor tyrosine kinase and has been approved by the Food and Drug Administration for treatment of non-small cell lung cancer.6 Interestingly, the epidermal growth factor receptor does not appear to be expressed in AML cells, indicating that the differentiation-inducing effects of gefitinib are likely due to inhibition of, as yet unidentified, cellular tyrosine kinases.5 The inhibition of a variety of cellular kinases by low micromolar concentrations of gefitinib has been reported.7 Despite an unclear mechanism of action, we sought to determine whether gefinitib might act in synergy with low-dose ATRA to stimulate myeloid differentiation.

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Authors and Affiliations

  1. Department of Medicine, University of Pittsburgh and the University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    M B Miranda, R Duan, R L Redner, J E Jones & D E Johnson

  2. Department of Otolaryngology, University of Pittsburgh and the University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    S M Thomas & J R Grandis

  3. Department of Pharmacology, University of Pittsburgh and the University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA

    J R Grandis & D E Johnson

Authors
  1. M B Miranda
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  2. R Duan
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  3. S M Thomas
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  4. J R Grandis
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  5. R L Redner
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  6. J E Jones
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  7. D E Johnson
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Correspondence to D E Johnson.

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Miranda, M., Duan, R., Thomas, S. et al. Gefitinib potentiates myeloid cell differentiation by ATRA. Leukemia 22, 1624–1627 (2008). https://doi.org/10.1038/leu.2008.28

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