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

Author:

Boehrer Simone123,Adès Lionel1234,Braun Thorsten124,Galluzzi Lorenzo123,Grosjean Jennifer12,Fabre Claire12,Le Roux Génèviève4,Gardin Claude4,Martin Antoine4,de Botton Stéphane2,Fenaux Pierre1234,Kroemer Guido123

Affiliation:

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

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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