Related Experiment Video

Updated: Sep 26, 2025

A Semi-High-Throughput Adaptation of the NADH-Coupled ATPase Assay for Screening Small Molecule Inhibitors
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Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

Kristin M Zimmerman Savill1,2, Brian B Lee1, Jason Oeh1

  • 1Department of Molecular Oncology, Genentech Inc., South San Francisco, CA, USA.

Nature Communications
|April 20, 2022
PubMed

Insights

Resistance to AKT inhibitors in prostate cancer varies. Allosteric inhibitor resistance involves AKT changes, while ATP-competitive inhibitor resistance involves rewiring signaling pathways. Combination therapies may overcome resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The AKT pathway is a key target in cancer therapy.
  • Both allosteric and ATP-competitive AKT inhibitors are under clinical investigation.
  • Acquired resistance can limit the long-term efficacy of these inhibitors.

Purpose of the Study:

  • To establish and characterize prostate cancer models of acquired resistance to distinct AKT inhibitors.
  • To elucidate the distinct molecular mechanisms driving resistance to allosteric versus ATP-competitive AKT inhibition.
  • To explore combination strategies for overcoming AKT inhibitor resistance.

Main Methods:

  • Development of prostate cancer models with acquired resistance to MK-2206 (allosteric) or ipatasertib (ATP-competitive) via prolonged drug exposure.
  • Analysis of molecular alterations and signaling pathway rewiring in resistant models.
  • In vivo testing of monotherapy and combination treatment strategies.

Main Results:

  • Resistance to the allosteric inhibitor MK-2206 was associated with alterations in AKT.
  • Resistance to the ATP-competitive inhibitor ipatasertib was driven by compensatory activation of parallel signaling pathways.
  • MK-2206 resistance was overcome by ipatasertib treatment.
  • Ipatasertib resistance was reversed by co-treatment with PIM signaling inhibitors.

Conclusions:

  • Distinct resistance mechanisms emerge against different classes of AKT inhibitors.
  • Targeting compensatory signaling pathways, such as PIM, can overcome resistance to ATP-competitive AKT inhibitors.
  • Combination therapy approaches hold promise for enhancing the durability of AKT inhibitor treatment in prostate cancer.

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