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

Simone Boehrer, Lionel Adès, Thorsten Braun, Lorenzo Galluzzi, Jennifer Grosjean, Claire Fabre, Génèviève Le Roux, Claude Gardin, Antoine Martin, Stéphane De Botton, Pierre Fenaux, Guido Kroemer

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    100 Citations (Scopus)

    Résumé

    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 AMLpatients while sparing normal CD34+ progenitors. This ex vivo therapeutic effect was once more associated with the nucleocytoplasmic translocation of NPM-1 and p14 ARF. 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.

    langue originaleAnglais
    Pages (de - à)2170-2180
    Nombre de pages11
    journalBlood
    Volume111
    Numéro de publication4
    Les DOIs
    étatPublié - 15 févr. 2008

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