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Nat Chem Biol. 2018 Aug;14(8):768-777. doi: 10.1038/s41589-018-0081-9. Epub 2018 Jun 25.

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

Author information

1
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA.
2
Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, USA.
3
Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
4
Center for Spatial Systems Biology, Oregon Health and Sciences University, Portland, OR, USA.
5
Howard Hughes Medical Institute, University of California San Francisco, San Francisco, CA, USA.
6
Department of Medicine, University of California San Francisco, San Francisco, CA, USA. john.gordan@ucsf.edu.
7
Department of Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, CA, USA. sourav.bandyopadhyay@ucsf.edu.

Abstract

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest, possibly because of dynamic changes in cellular signaling that drive resistance and limit drug efficacy. Using a quantitative chemoproteomics approach, we mapped kinome dynamics in response to inhibitors of this pathway and identified signaling changes that correlate with drug sensitivity. Maintenance of AURKA after drug treatment was associated with resistance in breast cancer models. Incomplete inhibition of AURKA was a common source of therapy failure, and combinations of PI3K, AKT or mTOR inhibitors with the AURKA inhibitor MLN8237 were highly synergistic and durably suppressed mTOR signaling, resulting in apoptosis and tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of targeted therapies and reveals new drug combinations that may unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.

PMID:
29942081
PMCID:
PMC6051919
DOI:
10.1038/s41589-018-0081-9
[Indexed for MEDLINE]
Free PMC Article

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