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Therapeutic resistance in acute myeloid leukemia cells is mediated by a novel ATM/mTOR pathway regulating oxidative phosphorylation. | LitMetric

AI Article Synopsis

  • Leukemic cells often resist treatment because their bone marrow environment protects them from drugs, making it essential to study how this protection occurs.
  • This research identifies that oxidative phosphorylation activation causes resistance in FLT3 mutant AML cells when treated with FLT3 inhibitors, which is linked to the activation of ATM and mTOR signaling.
  • Combining the mTOR inhibitor everolimus with the FLT3 inhibitor quizartinib significantly reduces tumor growth and prevents relapse in AML models, suggesting a new strategy for treating resistant FLT3 mutant AML.

Article Abstract

While leukemic cells are susceptible to various therapeutic insults, residence in the bone marrow microenvironment typically confers protection from a wide range of drugs. Thus, understanding the unique molecular changes elicited by the marrow is of critical importance toward improving therapeutic outcomes. In this study, we demonstrate that aberrant activation of oxidative phosphorylation serves to induce therapeutic resistance in FLT3 mutant human AML cells challenged with FLT3 inhibitor drugs. Importantly, our findings show that AML cells are protected from apoptosis following FLT3 inhibition due to marrow-mediated activation of ATM, which in turn upregulates oxidative phosphorylation via mTOR signaling. mTOR is required for the bone marrow stroma-dependent maintenance of protein translation, with selective polysome enrichment of oxidative phosphorylation transcripts, despite FLT3 inhibition. To investigate the therapeutic significance of this finding, we tested the mTOR inhibitor everolimus in combination with the FLT3 inhibitor quizartinib in primary human AML xenograft models. While marrow resident AML cells were highly resistant to quizartinib alone, the addition of everolimus induced profound reduction in tumor burden and prevented relapse. Taken together, these data provide a novel mechanistic understanding of marrow-based therapeutic resistance and a promising strategy for improved treatment of FLT3 mutant AML patients.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9645811PMC
http://dx.doi.org/10.7554/eLife.79940DOI Listing

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