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

Hayley J. Donnella, James T. Webber, Rebecca S. Levin, Roman Camarda, Olga Momcilovic, Nora Bayani, Khyati N. Shah, James Korkola, Kevan M. Shokat, Andrei Goga, John D. Gordan, Sourav Bandyopadhyay

Research output: Contribution to journalArticle

11 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-10
Number of pages10
JournalNature Chemical Biology
DOIs
StateAccepted/In press - Jun 25 2018

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Aurora Kinase A
Phosphatidylinositol 3-Kinases
Breast Neoplasms
Drug Combinations
Drug Delivery Systems
Drug Resistance
Pharmaceutical Preparations
Therapeutics
Maintenance
Apoptosis
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Donnella, H. J., Webber, J. T., Levin, R. S., Camarda, R., Momcilovic, O., Bayani, N., ... Bandyopadhyay, S. (Accepted/In press). Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer. Nature Chemical Biology, 1-10. https://doi.org/10.1038/s41589-018-0081-9

Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer. / Donnella, Hayley J.; Webber, James T.; Levin, Rebecca S.; Camarda, Roman; Momcilovic, Olga; Bayani, Nora; Shah, Khyati N.; Korkola, James; Shokat, Kevan M.; Goga, Andrei; Gordan, John D.; Bandyopadhyay, Sourav.

In: Nature Chemical Biology, 25.06.2018, p. 1-10.

Research output: Contribution to journalArticle

Donnella, HJ, Webber, JT, Levin, RS, Camarda, R, Momcilovic, O, Bayani, N, Shah, KN, Korkola, J, Shokat, KM, Goga, A, Gordan, JD & Bandyopadhyay, S 2018, 'Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer', Nature Chemical Biology, pp. 1-10. https://doi.org/10.1038/s41589-018-0081-9
Donnella, Hayley J. ; Webber, James T. ; Levin, Rebecca S. ; Camarda, Roman ; Momcilovic, Olga ; Bayani, Nora ; Shah, Khyati N. ; Korkola, James ; Shokat, Kevan M. ; Goga, Andrei ; Gordan, John D. ; Bandyopadhyay, Sourav. / Kinome rewiring reveals AURKA limits PI3K-pathway inhibitor efficacy in breast cancer. In: Nature Chemical Biology. 2018 ; pp. 1-10.
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