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<p>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 <i>EGR1</i> 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 <i>EGR1</i> 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 <i>EGR1</i> not only as a biomarker of treatment response, but also as a potential target for future therapeutic interventions, offering valuable insights for patient management.</p>

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Combinational BET and mTOR inhibition unveils EGR1 as acute myeloid leukemia prognostic biomarker

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • Marcela Teatin Latancia,
  • Wellington Fernandes da Silva,
  • Elayne Bragança-Jardim,
  • Fernanda Fernandes Terra,
  • Paula Fontes Asprino,
  • Welbert De Oliveira Pereira,
  • Vanessa Candiotti Buzatto,
  • Pedro Alexandre Galante,
  • Lilian Tiemi Inoue,
  • Ana Rita Fonseca,
  • Thais Nascimento Kimmemgs,
  • Celso Arrais-Rodrigues,
  • Vanderson Rocha,
  • Yana Novis,
  • Niels Olsen Saraiva Camara,
  • Ana Paula Lepique,
  • Luiz Fernando Lima Reis,
  • Mariane Tami Amano

摘要

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.