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Blood, 15 February 2008, Vol. 111, No. 4, pp. 2170-2180.
Prepublished online as a Blood First Edition Paper on October 9, 2007November 21, 2007; DOI 10.1182/blood-2007-07-100362.
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Submitted July 9, 2007
Accepted September 25, 2007
Erlotinib exhibits anti-neoplastic off-target effects in AML and MDS: a preclinical study
Simone Boehrer, Lionel Ades, Thorsten Braun, Lorenzo Galluzzi, Jennifer Grosjean, Claire Fabre, Genevieve Le Roux, Claude Gardin, Antoine Martin, Stephane de Botton, Pierre Fenaux, and Guido Kroemer*
INSERM, U848, 94805, Villejuif, France
Institut Gustave Roussy, 94805, Villejuif, France
Service d'Hematologie Clinique, Hopital Avicenne, AP-HP, Universite Paris XIII, Bobigny, France
Universite Paris-Sud/Paris XI, Paris, France
* Corresponding author; email: kroemer{at}igr.fr.
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 occured independently from phenotypic differentiation. In apoptosis-sensitive AML cells, erlotinib caused a rapid 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 hematological 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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