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Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer

Hayley J Donnella1, James T Webber1, Rebecca S Levin2

  • 1Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.

Nature Chemical Biology
|June 27, 2018
PubMed

Insights

Targeting the PI3K-AKT-mTOR pathway in breast cancer shows promise. Combining pathway inhibitors with AURKA inhibitors overcomes resistance, enhancing apoptosis and tumor regression for improved treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The PI3K-AKT-mTOR signaling network is frequently dysregulated in breast cancer.
  • Current targeted therapies for this pathway show limited clinical efficacy due to resistance.
  • Dynamic signaling changes contribute to therapeutic resistance and reduced drug effectiveness.

Purpose of the Study:

  • To map kinome dynamics in response to PI3K-AKT-mTOR pathway inhibitors.
  • To identify signaling alterations associated with drug sensitivity and resistance.
  • To discover novel drug combinations to enhance breast cancer treatment.

Main Methods:

  • Quantitative chemoproteomics was employed to analyze signaling networks.
  • Kinome dynamics were mapped in breast cancer models under drug treatment.
  • Synergistic effects of combined PI3K/AKT/mTOR and AURKA inhibitors were evaluated.

Main Results:

  • Maintenance of Aurora Kinase A (AURKA) post-treatment correlated with resistance.
  • Incomplete AURKA inhibition was a key factor in therapy failure.
  • Combinations of PI3K, AKT, or mTOR inhibitors with MLN8237 (an AURKA inhibitor) demonstrated high synergy.
  • Combined therapy led to durable mTOR signaling suppression, apoptosis, and in vivo tumor regression.

Conclusions:

  • Signaling pathways, like AURKA, can limit the efficacy of targeted breast cancer therapies.
  • Combining PI3K-AKT-mTOR inhibitors with AURKA inhibitors offers a promising strategy.
  • This approach may overcome resistance and improve outcomes for breast cancer patients.

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