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

Nat Chem Biol 2018 08 25;14(8):768-777. Epub 2018 Jun 25.

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

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41589-018-0081-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051919PMC
August 2018

Publication Analysis

Top Keywords

breast cancer
12
signaling
5
inhibition aurka
4
aurka common
4
incomplete inhibition
4
resistance breast
4
cancer models
4
models incomplete
4
common source
4
source therapy
4
mtor inhibitors
4
inhibitors aurka
4
akt mtor
4
pi3k akt
4
failure combinations
4
combinations pi3k
4
therapy failure
4
associated resistance
4
inhibitors pathway
4
pathway identified
4

Similar Publications