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
p14(ARF). 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
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.