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 Blood, 15 February 2008, Vol. 111, No. 4, pp. 2170-2180.
Prepublished online as a Blood First Edition Paper on November 21, 2007; DOI 10.1182/blood-2007-07-100362.

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NEOPLASIA

Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study

Simone Boehrer1,3, Lionel Adès1,4, Thorsten Braun1,2,4, Lorenzo Galluzzi1,3, Jennifer Grosjean1,2, Claire Fabre1,2, Génèviève Le Roux4, Claude Gardin4, Antoine Martin4, Stéphane de Botton2, Pierre Fenaux1,4, and Guido Kroemer1,3

1 Inserm, U848, Villejuif; 2 Institut Gustave Roussy, Villejuif; 3 Université Paris-Sud, Paris; and 4 Service d'Hématologie Clinique, Hôpital Avicenne, Université Paris XIII, Bobigny, France

Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR), induces differentiation, cell-cycle arrest, and apoptosis of EGFR-negative myeloblasts of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as in EGFR-negative cell lines representing these diseases (P39, KG-1, and HL 60). This off-target effect can be explained by inhibitory effects on JAK2. Apoptosis induction coupled to mitochondrial membrane permeabilization occurred independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid (within less than 1 hour) nucleocytoplasmic translocation of nucleophosmin-1 (NPM-1) and p14ARF. Apoptosis-insensitive myeloblasts failed to manifest this translocation yet became sensitive to apoptosis induction by erlotinib when NPM-1 was depleted by RNA interference. Moreover, erlotinib reduced the growth of xenografted human AML cells in vivo. Erlotinib also killed CD34+ bone marrow blasts from MDS and AML patients while sparing normal CD34+ progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14ARF. One patient afflicted with both MDS and non–small cell lung cancer manifested hematologic improvement in response to erlotinib. In summary, we here provide novel evidence in vitro, ex vivo, and in vivo for the potential therapeutic efficacy of erlotinib in the treatment of high-risk MDS and AML.


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