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Combinational BET and mTOR inhibition unveils EGR1 as acute myeloid leukemia prognostic biomarker
Marcela Teatin Latancia1, Wellington Fernandes da Silva2,3,4, Elayne Bragança-Jardim1
1Hospital Sírio-Libanes, R. Prof. Daher Cutait, 69, São Paulo, SP, Brazil.
Abstract:
This study investigated the anti-leukemic potential of BET inhibitors in combination with mTOR inhibitors, focusing on both BET-resistant and BET-sensitive AML cell lines. Our findings reveal a significant suppression of proliferation and induction of apoptosis across all tested cell lines following combined treatment. Interestingly, JQ1 (a specific BET inhibitor) triggered cell cycle arrest only in sensitive cells when used alone while addition of mTOR inhibitors extended this antiproliferative effect to BET-resistant cells as well. This observation underscores the potential of this combination therapy to circumvent existing resistance mechanisms. This study further confirmed an additive antitumor effect of the combined inhibitors in primary AML patient cells. We also identified EGR1 as a predictive biomarker for treatment efficacy, which was correlated with increased levels of EGR1, a protein linked to enhanced overall survival. In silico analysis suggested better prognosis for AML patients with higher EGR1 expression. This study validates the combined use of BET and mTOR inhibitors as a promising treatment strategy for AML, capable of overcoming resistance and enhancing therapeutic outcomes. Furthermore, our investigation also highlights EGR1 not only as a biomarker of treatment response, but also as a potential target for future therapeutic interventions, offering valuable insights for patient management.
Insights
Combining BET and mTOR inhibitors shows promise against acute myeloid leukemia (AML). This therapy overcomes resistance and boosts anti-leukemic effects, with EGR1 identified as a key biomarker.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Acute myeloid leukemia (AML) remains a challenging hematologic malignancy.
- Developing novel therapeutic strategies to overcome drug resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the combined efficacy of BET inhibitors and mTOR inhibitors in AML.
- To explore the potential of this combination therapy in overcoming BET inhibitor resistance.
- To identify biomarkers predictive of treatment response.
Main Methods:
- Utilized BET-resistant and BET-sensitive AML cell lines for in vitro studies.
- Administered combination therapy of BET and mTOR inhibitors.
- Assessed cell proliferation, apoptosis, and cell cycle progression.
- Analyzed primary AML patient cells.
- Performed in silico analysis for biomarker validation.
Main Results:
- Combined BET and mTOR inhibitors significantly suppressed proliferation and induced apoptosis in all tested AML cell lines.
- The combination therapy extended antiproliferative effects to BET-resistant cells, circumventing resistance mechanisms.
- Additive antitumor effects were observed in primary AML patient cells.
- EGR1 was identified as a predictive biomarker for treatment efficacy and correlated with improved overall survival.
Conclusions:
- Combined BET and mTOR inhibitors represent a promising therapeutic strategy for AML, effectively overcoming resistance.
- EGR1 serves as a valuable predictive biomarker for treatment response and a potential therapeutic target in AML.
- This combination therapy offers enhanced therapeutic outcomes and improved patient management strategies for AML.
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