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Erlotinib exhibits antineoplastic off-target effects in AML and MDS: a preclinical study
Simone Boehrer1, Lionel Adès, Thorsten Braun
1Inserm, U848, Villejuif, 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 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.
Insights
Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, shows potential for treating myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) by inducing cancer cell death. This off-target effect involves JAK2 inhibition and nucleocytoplasmic translocation of NPM-1 and p14(ARF).
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Erlotinib is an epidermal growth factor receptor (EGFR) inhibitor.
- Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are hematologic malignancies.
- EGFR-negative myeloblasts in MDS and AML exhibit sensitivity to erlotinib.
Purpose of the Study:
- To investigate the therapeutic potential of erlotinib in high-risk MDS and AML.
- To elucidate the mechanisms underlying erlotinib's off-target effects in EGFR-negative leukemia cells.
- To evaluate erlotinib's efficacy in preclinical models and patient-derived samples.
Main Methods:
- In vitro studies using EGFR-negative cell lines (P39, KG-1, HL 60).
- Assessment of apoptosis, cell-cycle arrest, and nucleocytoplasmic translocation of NPM-1 and p14(ARF).
- In vivo studies using xenograft models and ex vivo analysis of patient bone marrow blasts.
Main Results:
- Erlotinib induced apoptosis and cell-cycle arrest in EGFR-negative MDS and AML cells, independent of phenotypic differentiation.
- The drug's effects were linked to JAK2 inhibition and rapid nucleocytoplasmic translocation of NPM-1 and p14(ARF) in sensitive cells.
- Erlotinib reduced tumor growth in vivo and selectively killed malignant blasts ex vivo while sparing normal progenitors.
Conclusions:
- Erlotinib demonstrates significant therapeutic potential for high-risk MDS and AML.
- The drug's efficacy is mediated through off-target effects, including JAK2 inhibition and modulation of NPM-1/p14(ARF) pathways.
- Erlotinib offers a promising targeted therapy option for specific patient populations in MDS and AML.
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