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Cancer Cell. 2015 Jan 12;27(1):97-108. doi: 10.1016/j.ccell.2014.11.007. Epub 2014 Dec 24.

Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer.

Author information

1
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA.
2
Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy.
3
Cell Signaling Technology, Inc., Danvers, MA 01923, USA.
4
Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
6
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. Electronic address: jengelman@partners.org.

Abstract

BYL719, which selectively inhibits the alpha isoform of the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110a), is currently in clinical trials for the treatment of solid tumors, especially luminal breast cancers with PIK3CA mutations and/or HER2 amplification. This study reveals that, even among these sensitive cancers, the initial efficacy of p110α inhibition is mitigated by rapid re-accumulation of the PI3K product PIP3 produced by the p110β isoform. Importantly, the reactivation of PI3K mediated by p110β does not invariably restore AKT phosphorylation, demonstrating the limitations of using phospho-AKT as a surrogate to measure PI3K activation. Consistently, we show that the addition of the p110β inhibitor to BYL719 prevents the PIP3 rebound and induces greater antitumor efficacy in HER2-amplified and PIK3CA mutant cancers.

PMID:
25544637
PMCID:
PMC4745884
DOI:
10.1016/j.ccell.2014.11.007
[Indexed for MEDLINE]
Free PMC Article

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