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JR-AB2-011 induces fast metabolic changes independent of mTOR complex 2 inhibition in human leukemia cells

Tereza Kořánová1, Lukáš Dvořáček1, Dana Grebeňová1

  • 1Department of Proteomics, Institute of Hematology and Blood Transfusion, U Nemocnice 1, Prague, 128 20, Czech Republic.

Pharmacological Reports : PR
|September 11, 2024
PubMed
Abstract

Insights

The mTORC2 inhibitor JR-AB2-011 impacts leukemia cell metabolism independently of mTORC2, affecting respiration and glycolysis. This finding challenges its proposed mechanism of action in cancer cells.

Area of Science:

  • Cellular metabolism
  • Oncology
  • Molecular signaling

Background:

  • The mechanistic target of rapamycin (mTOR) pathway regulates cellular metabolic activity and is often dysregulated in leukemia/lymphoma.
  • Specific inhibitors are needed to elucidate the distinct roles of mTOR complexes (mTORC1 and mTORC2).
  • JR-AB2-011 was reported as an mTORC2-specific inhibitor, targeting mTOR interaction with RICTOR.

Purpose of the Study:

  • To investigate the effects of JR-AB2-011 on leukemia and lymphoma cell metabolism.
  • To determine if JR-AB2-011 functions as an mTORC2 inhibitor in these cell types.

Main Methods:

  • Seahorse platform used to analyze cellular metabolism.
  • Assessed AKT Ser473 phosphorylation as an indicator of mTORC2 activity.
  • Utilized co-immunoprecipitation to evaluate mTOR-RICTOR binding and CRISPR/Cas9 to generate RICTOR-null cells.

Main Results:

  • JR-AB2-011 decreased respiration and increased glycolysis in leukemia/lymphoma cell lines.
  • Contrary to expectations, JR-AB2-011 did not inhibit AKT Ser473 phosphorylation or disrupt mTOR-RICTOR binding.
  • Metabolic effects of JR-AB2-011 were observed even in RICTOR-null cells, indicating an mTORC2-independent mechanism.

Conclusions:

  • JR-AB2-011 modulates leukemia/lymphoma cell metabolism through a pathway not involving mTORC2.
  • The study reveals a novel mechanism of action for JR-AB2-011, distinct from its presumed mTORC2 inhibition.
Keywords:
AMLAcute myeloid leukemiaMitochondrial respirationOCR

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